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Ploumaki I, Macri VI, Segars JH, Islam MS. Progesterone signaling in uterine fibroids: Molecular mechanisms and therapeutic opportunities. Life Sci 2025; 362:123345. [PMID: 39740758 PMCID: PMC11755406 DOI: 10.1016/j.lfs.2024.123345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 01/02/2025]
Abstract
Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.
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Affiliation(s)
- Ioanna Ploumaki
- School of Medicine at National and Kapodistrian University of Athens, Athens 157 72, Greece
| | - Valeria I Macri
- Department of Gynecology and Obstetrics, Division of Reproductive Sciences & Women's Health Research, Johns Hopkins Medicine, Baltimore, MD 21205, USA
| | - James H Segars
- Department of Gynecology and Obstetrics, Division of Reproductive Sciences & Women's Health Research, Johns Hopkins Medicine, Baltimore, MD 21205, USA
| | - Md Soriful Islam
- Department of Gynecology and Obstetrics, Division of Reproductive Sciences & Women's Health Research, Johns Hopkins Medicine, Baltimore, MD 21205, USA.
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2
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Ji F, Zhang J, Mao L, Tan Y, Ye M, He X, Zhao Y, Liu J, Zhang Y, Zhang N, Shi J, Yan J, Cai X, Zhao B, Jin J, Xu P, Roessler S, Zheng X, Ji J. Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation. Nat Commun 2025; 16:50. [PMID: 39747098 PMCID: PMC11696091 DOI: 10.1038/s41467-024-55745-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
Roles of liver-specific genes (LSGs) in tumor initiation and progression are rarely explored in hepatocellular carcinoma (HCC). Here we show that LSGs are generally downregulated in HCC tumor tissues compared to non-HCC liver tissues, and low-LSG HCCs show poor prognosis and the activated c-Myc pathway. Among the c-Myc- and patient prognosis-associated LSGs, PGRMC1 significantly blocks c-Myc-induced orthotopic HCC formation. The role of PGRMC1 depends on its localization to the endoplasmic reticulum (ER) membrane, where PGRMC1 interacts with PERK through their ER luminal domains. This interaction in turn activates PERK in an ER stress-independent manner, which phosphorylates eIF2α and consequently inhibits c-Myc protein translation. In HCC patients, PGRMC1 level is significantly reduced in tumor tissues and negatively associated with the c-Myc signature. Patients with low-PGRMC1 in their tumors have poor prognosis. Collectively, deregulated LSGs in HCC are associated with the c-Myc pathway activation and PGRMC1 blocks c-Myc-induced hepatic carcinogenesis through promoting ER stress-independent PERK activation.
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Affiliation(s)
- Fubo Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Jianjuan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Liping Mao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yaqi Tan
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Meihua Ye
- Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310000, China
| | - Xianglei He
- Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310000, China
| | - Yongzhi Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Jiaxin Liu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Nachuan Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Jiong Shi
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Jianing Yan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Bin Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Jianping Jin
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Pinglong Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Xin Zheng
- Taoharmony Biotech L.L.C., Hangzhou, Zhejiang, 310018, China
| | - Junfang Ji
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
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3
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Meng FZ, Wei WK, Cai MZ, Wang ZQ, Yin LF, Yin WX, Schnabel G, Luo CX. The Mediator complex subunit MoMed15 plays an important role in conferring sensitivity to isoprothiolane by modulating xenobiotic metabolism in M. oryzae. mBio 2024; 15:e0177824. [PMID: 39530687 PMCID: PMC11633134 DOI: 10.1128/mbio.01778-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/13/2024] [Indexed: 11/16/2024] Open
Abstract
Rice blast caused by Magnaporthe oryzae is one of the most economically important rice diseases. Fungicides such as isoprothiolane (IPT) have been used extensively for rice blast control, but resistance to IPT in M. oryzae is an emerging threat. In this study, molecular mechanisms of resistance in IPT-resistant mutants were identified. Through whole-genome sequencing and genetic transformation, we identified the gene MoMed15, encoding a transcriptional glutamine-rich co-activator Mediator complex subunit, in which mutations or deletion resulted in moderate IPT resistance. Further research found that MoMed15 physically interacted with the IPT resistance regulatory factor MoIRR to simultaneously regulate both MoIRR expression and the expression of multiple xenobiotic-metabolizing enzymes in response to IPT stress. We hypothesize that some xenobiotic-metabolizing enzymes enhance IPT toxicity by modifying the IPT structure. Variation of MoMed15 affected the recruitment of the transcriptional Mediator complex and decreased the expression of these xenobiotic-metabolizing enzymes, resulting in moderate IPT resistance. We also found that MoPGR1, encoding a protein that activates cytochrome P450 enzymes, was essential to confer IPT sensitivity, and its expression was directly regulated by MoIRR.IMPORTANCEIsoprothiolane (IPT) has been used extensively for the management of rice blast disease and IPT-resistant subpopulations have emerged in Chinese rice fields. The emergence of resistant pathogen populations has led to a steep increase in fungicide use, increasing pesticide risk for the applicator and the environment. The molecular mechanisms of IPT resistance in M. oryzae remain elusive. In this study, we demonstrated that transcriptional co-activator MoMed15 interacts with IPT resistance regulator MoIRR to recruit the Mediator complex, which promotes the expression of xenobiotic-metabolizing enzymes, leading to exacerbated IPT toxicity. The MoMed15 could be used for IPT resistance detection in rice fields.
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Affiliation(s)
- Fan-Zhu Meng
- Hubei Key Lab of Plant Pathology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Wen-Kai Wei
- Hubei Key Lab of Plant Pathology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Min-Zheng Cai
- Hubei Key Lab of Plant Pathology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Zuo-Qian Wang
- Institute of Plant Protection and Soil Science, Hubei Academy of Agricultural Sciences, Wuhan, China
| | - Liang-Fen Yin
- Experimental Teaching Center of Crop Science, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Wei-Xiao Yin
- Hubei Key Lab of Plant Pathology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Guido Schnabel
- Department of Plant and Environmental Sciences, Clemson University, Clemson, South Carolina, USA
| | - Chao-Xi Luo
- Hubei Key Lab of Plant Pathology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
- Experimental Teaching Center of Crop Science, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China
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4
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Sergejevs N, Avci D, van de Weijer ML, Corey RA, Lemberg MK, Carvalho P. Topology surveillance of the lanosterol demethylase CYP51A1 by signal peptide peptidase. J Cell Sci 2024; 137:jcs262333. [PMID: 39513424 PMCID: PMC11827857 DOI: 10.1242/jcs.262333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024] Open
Abstract
Cleavage of transmembrane segments on target proteins by the aspartyl intramembrane protease signal peptide peptidase (SPP, encoded by HM13) has been linked to immunity, viral infection and protein quality control. How SPP recognizes its various substrates and specifies their fate remains elusive. Here, we identify the lanosterol demethylase CYP51A1 as an SPP substrate and show that SPP-catalysed cleavage triggers CYP51A1 clearance by endoplasmic reticulum-associated degradation (ERAD). We observe that SPP targets only a fraction of CYP51A1 molecules, and we identify an amphipathic helix in the CYP51A1 N terminus as a key determinant for SPP recognition. SPP recognition is remarkably specific to CYP51A1 molecules with the amphipathic helix aberrantly inserted in the membrane with a type II orientation. Thus, our data are consistent with a role for SPP in topology surveillance, triggering the clearance of certain potentially non-functional conformers.
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Affiliation(s)
- Nikita Sergejevs
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
| | - Dönem Avci
- Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Michael L. van de Weijer
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
| | - Robin A. Corey
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - Marius K. Lemberg
- Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Pedro Carvalho
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
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5
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Guengerich FP. Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism. Pharmacol Rev 2024; 76:1104-1132. [PMID: 39054072 PMCID: PMC11549934 DOI: 10.1124/pharmrev.124.001173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/28/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024] Open
Abstract
Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"]. SIGNIFICANCE STATEMENT: Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.
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Affiliation(s)
- F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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6
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Guan A, Dai Z, Jiang C, Sun J, Yang B, Xie B, Chen Q. PGRMC1 promotes NSCLC stemness phenotypes by disrupting TRIM56-mediated ubiquitination of AHR. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167440. [PMID: 39059592 DOI: 10.1016/j.bbadis.2024.167440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Cancer stem cells (CSCs) are responsible for tumor chemoresistance, and the aryl hydrocarbon receptor (AHR) is indispensable for maintaining CSC characteristics. Here, we aimed to investigate how the interaction between progesterone receptor membrane component 1 (PGRMC1) and AHR contributes to the maintenance of CSC phenotypes in non-small cell lung cancer (NSCLC). Clinical data and tissue microarray analyses indicated that patients with elevated PGRMC1 expression had poorer prognoses. Moreover, PGRMC1 overexpression enhanced CSC phenotypes and chemotherapy resistance in vitro and in vivo by modulating AHR ubiquitination. We then determined the specific interaction sites between PGRMC1 and AHR. Mass spectrometry screening identified tripartite motif containing 56 (TRIM56) as the E3 ligase targeting AHR. Notably, PGRMC1 overexpression inhibited the interaction between TRIM56 and AHR. Overall, our study revealed a regulatory mechanism that involves PGRMC1, AHR, and TRIM56, providing insights for developing CSC-targeting strategies in NSCLC treatment.
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MESH Headings
- Animals
- Female
- Humans
- Male
- Mice
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/genetics
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Gene Expression Regulation, Neoplastic
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Lung Neoplasms/genetics
- Membrane Proteins/metabolism
- Membrane Proteins/genetics
- Mice, Nude
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Phenotype
- Receptors, Aryl Hydrocarbon/metabolism
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Progesterone/metabolism
- Tripartite Motif Proteins/metabolism
- Tripartite Motif Proteins/genetics
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
- Ubiquitination
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Affiliation(s)
- Anqi Guan
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ziyu Dai
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chen Jiang
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jingyi Sun
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Baishuang Yang
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Bin Xie
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Qiong Chen
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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7
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Belot A, Puy H, Hamza I, Bonkovsky HL. Update on heme biosynthesis, tissue-specific regulation, heme transport, relation to iron metabolism and cellular energy. Liver Int 2024; 44:2235-2250. [PMID: 38888238 PMCID: PMC11625177 DOI: 10.1111/liv.15965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 06/20/2024]
Abstract
Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen-carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life. In mammals, heme is synthesised from glycine, succinyl-CoA, and ferrous iron in a series of eight steps. The first and normally rate-controlling step is catalysed by 5-aminolevulinate synthase (ALAS), which has two forms: ALAS1 is the housekeeping form with highly variable expression, depending upon the supply of the end-product heme, which acts to repress its activity; ALAS2 is the erythroid form, which is regulated chiefly by the adequacy of iron for erythroid haemoglobin synthesis. Abnormalities in the several enzymes of the heme synthetic pathway, most of which are inherited partial enzyme deficiencies, give rise to rare diseases called porphyrias. The existence and role of heme importers and exporters in mammals have been debated. Recent evidence established the presence of heme transporters. Such transporters are important for the transfer of heme from mitochondria, where the penultimate and ultimate steps of heme synthesis occur, and for the transfer of heme from cytoplasm to other cellular organelles. Several chaperones of heme and iron are known and important for cell health. Heme and iron, although promoters of oxidative stress and potentially toxic, are essential cofactors for cellular energy production and oxygenation.
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Affiliation(s)
- Audrey Belot
- Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Herve Puy
- Centre Français des Porphyries, Assistance Publique-Hôpitaux de Paris (APHP), Université de Paris Cité, INSERM U1149, Paris, France
| | - Iqbal Hamza
- Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA
| | - Herbert L. Bonkovsky
- Section on Gastroenterology & Hepatology, Department of Medicine, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA
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8
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Stefanski KM, Wilkinson MC, Sanders CR. Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease. Biochem Soc Trans 2024; 52:1747-1756. [PMID: 38979632 PMCID: PMC11574964 DOI: 10.1042/bst20231359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/03/2024] [Accepted: 06/13/2024] [Indexed: 07/10/2024]
Abstract
Underexpression, overexpression, and point mutations in peripheral myelin protein 22 (PMP22) cause most cases of Charcot-Marie-Tooth disease (CMTD). While its exact functions remain unclear, PMP22 is clearly essential for formation and maintenance of healthy myelin in the peripheral nervous system. This review explores emerging evidence for roles of PMP22 in cholesterol homeostasis. First, we highlight dysregulation of lipid metabolism in PMP22-based forms of CMTD and recently-discovered interactions between PMP22 and cholesterol biosynthesis machinery. We then examine data that demonstrates PMP22 and cholesterol co-traffic in cells and co-localize in lipid rafts, including how disease-causing PMP22 mutations result in aberrations in cholesterol localization. Finally, we examine roles for interactions between PMP22 and ABCA1 in cholesterol efflux. Together, this emerging body of evidence suggests that PMP22 plays a role in facilitating enhanced cholesterol synthesis and trafficking necessary for production and maintenance of healthy myelin.
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Affiliation(s)
- Katherine M Stefanski
- Department of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37240-7917, U.S.A
| | - Mason C Wilkinson
- Department of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37240-7917, U.S.A
| | - Charles R Sanders
- Department of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37240-7917, U.S.A
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9
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Barata IS, Rueff J, Kranendonk M, Esteves F. Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity. J Xenobiot 2024; 14:575-603. [PMID: 38804287 PMCID: PMC11130977 DOI: 10.3390/jox14020034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b5 (cyt b5)'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).
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Affiliation(s)
- Isabel S. Barata
- Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland;
- Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - José Rueff
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
| | - Michel Kranendonk
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
| | - Francisco Esteves
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
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10
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Xu D, Wang M, Zhang X, Mao H, Xu H, Zhang B, Zeng X, Li F. The Putative Cytochrome b5 Domain-Containing Protein CaDap1 Homologue Is Involved in Antifungal Drug Tolerance, Cell Wall Chitin Maintenance, and Virulence in Candida albicans. J Fungi (Basel) 2024; 10:316. [PMID: 38786671 PMCID: PMC11122062 DOI: 10.3390/jof10050316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024] Open
Abstract
Candida albicans (Ca), a prominent opportunistic fungal pathogen in humans, has garnered considerable attention due to its infectious properties. Herein, we have identified and characterized CaCDAP1 (Ca orf19.1034), a homolog of ScDAP1 found in Saccharomyces cerevisiae. CaCDAP1 encodes a 183-amino acid protein with a conserved cytochrome b5-like heme-binding domain. The deletion of CaDAP1 renders Ca cells susceptible to caspofungin and terbinafine. CaDAP1 deletion confers resistance to Congo Red and Calcofluor White, and sensitivity to sodium dodecyl sulfate. The deletion of CaDAP1 results in a 50% reduction in chitin content within the cell wall, the downregulation of phosphorylation levels in CaMkc1, and the upregulation of phosphorylation levels in CaCek1. Notably, CaDAP1 deletion results in the abnormal hyphal development of Ca cells and diminishes virulence in a mouse systemic infection model. Thus, CaDAP1 emerges as a critical regulator governing cellular responses to antifungal drugs, the synthesis of cell wall chitin, and virulence in Ca.
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Affiliation(s)
- Dayong Xu
- College of Life Sciences, Huaibei Normal University, Huaibei 235000, China; (M.W.); (X.Z.); (H.M.); (H.X.); (B.Z.); (X.Z.)
| | | | | | | | | | | | | | - Feng Li
- College of Life Sciences, Huaibei Normal University, Huaibei 235000, China; (M.W.); (X.Z.); (H.M.); (H.X.); (B.Z.); (X.Z.)
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11
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Ucar EH, Peker C, Hitit M, Kose M, Tatar M, Bozkaya F, Atli MO. Altered luteal expression patterns of genomic and non-genomic progesterone receptors in bitches at different reproductive states. Theriogenology 2024; 218:153-162. [PMID: 38325152 DOI: 10.1016/j.theriogenology.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/16/2024] [Accepted: 02/01/2024] [Indexed: 02/09/2024]
Abstract
The binding of steroid hormones to their specific receptors is necessary to exert their effects on target cells. Progesterone (P4), a steroid hormone, carries out its effects through both genomic and non-genomic (the cell membrane-associated) receptors. This study aimed to ascertain luteal expression patterns of genomic and non-genomic progesterone receptors in bitches in physiological (early dioestrus and early pregnant) and pathological (pyometra) reproductive states. Luteal tissue was collected from the bitches at early dioestrus (ED, n = 5), early pregnant (EP, n = 5), and pyometra (PY, n = 5). The expression profiles of Steroidogenic Acute Regulator Protein (STAR), Progesterone Receptor (PGR), Membrane Progestin Receptors (PAQR5, PAQR7 and PAQR8), and Progesterone Membrane Components (PGMRC1 and PGMRC2) were examined at the mRNA levels using Real-Time Polymerase Chain Reaction (RT-PCR). Protein levels of PGR, PGMRC1 and PGMRC2 were detected by western blotting (WB). The STAR expression was found in all groups, with a statistical difference observed between EP and PY groups (P < 0.05). The protein level of PGR was determined to be highest in the EP group and lowest in the PY group. The expression of PAQR8 increased in the EP group (P < 0.05). The PAQR5 exhibited high expression in the EP group and low expression in the PY group (P < 0.05). PGRMC1 was more elevated in the EP group and lower in the PY group (P < 0.05). Protein levels of PGMRC1 and PGMRC2 were also observed at the highest expression in EP group. According to the altered expression profiles for examined receptors, we suggest that those progesterone receptors have roles in early pregnancy or pyometra in bitches.
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Affiliation(s)
- Eyyup Hakan Ucar
- Aydin Adnan Menderes University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Aydin, Turkey.
| | - Cevdet Peker
- Aydin Adnan Menderes University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Aydin, Turkey.
| | - Mustafa Hitit
- Kastamonu University, Faculty of Veterinary Medicine, Department of Animal Genetics, Kastamonu, Turkey; Prairie View University, College of Agriculture, Food and Human Sciences, Prairie View, TX, USA.
| | - Mehmet Kose
- Dicle University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Diyarbakir, Turkey.
| | - Musa Tatar
- Kastamonu University, Faculty of Veterinary Medicine, Department of Histology and Emrbyology, Kastamonu, Turkey.
| | - Faruk Bozkaya
- Harran University, Faculty of Veterinary Medicine, Department of Animal Science and Animal Nutrition/Department of Veterinary Genetics, Sanliurfa, Turkey.
| | - Mehmet Osman Atli
- Harran University, Faculty of Veterinary Medicine, Department of Reproduction and Artificial Inseminatio, Sanliurfa, Turkey.
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12
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Sanchez-Guerrero G, Umbaugh DS, Ramachandran AA, Artigues A, Jaeschke H, Ramachandran A. Translocation of Adenosine A2B Receptor to Mitochondria Influences Cytochrome P450 2E1 Activity after Acetaminophen Overdose. LIVERS 2024; 4:15-30. [PMID: 39007013 PMCID: PMC11245301 DOI: 10.3390/livers4010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/16/2024] Open
Abstract
The adenosine A2B receptor (A2BAR) is a member of a family of G-protein coupled receptors (GPCRs), which has a low affinity for adenosine and is now implicated in several pathophysiological conditions. We have demonstrated the beneficial effects of A2BAR activation in enhancing recovery after acute liver injury induced by an acetaminophen (APAP) overdose. While receptor trafficking within the cell is recognized to play a role in GPCR signaling, its role in the mediation of A2BAR effects in the context of APAP-induced liver injury is not well understood. This was investigated here, where C57BL/6J mice were subjected to an APAP overdose (300 mg/kg), and the temporal course of A2BAR intracellular localization was examined. The impact of A2BAR activation or inhibition on trafficking was examined by utilizing the A2BAR agonist BAY 60-6583 or antagonist PSB 603. The modulation of A2BAR trafficking via APAP-induced cell signaling was explored by using 4-methylpyrazole (4MP), an inhibitor of Cyp2E1 and JNK activation. Our results indicate that APAP overdose induced the translocation of A2BAR to mitochondria, which was prevented via 4MP treatment. Furthermore, we demonstrated that A2BAR is localized on the mitochondrial outer membrane and interacts with progesterone receptor membrane component 1 (PGRMC1). While the activation of A2BAR enhanced mitochondrial localization, its inhibition decreased PGRMC1 mitochondria levels and blunted mitochondrial Cyp2E1 activity. Thus, our data reveal a hitherto unrecognized consequence of A2BAR trafficking to mitochondria and its interaction with PGRMC1, which regulates mitochondrial Cyp2E1 activity and modulates APAP-induced liver injury.
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Affiliation(s)
- Giselle Sanchez-Guerrero
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
| | - David S. Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
| | - Abhay A. Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
| | - Antonio Artigues
- Department of Biochemistry, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
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13
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Thomas P, Pang Y, Kelder J. Membrane progesterone receptors on the cell membrane: A review highlighting potential export motifs in mPRα regulating its trafficking to the cell surface. Steroids 2023; 199:109295. [PMID: 37558174 DOI: 10.1016/j.steroids.2023.109295] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/03/2023] [Accepted: 08/05/2023] [Indexed: 08/11/2023]
Abstract
Substantial progress has been made in our understanding of the nongenomic actions, ligand binding, intracellular signaling pathways, and functions of membrane progesterone receptors (mPRs) in reproductive and nonreproductive tissues since their discovery 20 years ago. The five mPRs are members of the progestin adipoQ receptor (PAQR) family which also includes adiponectin receptors (AdipoRs). However, unlike AdipoRs, the 3-D structures of mPRs are unknown, and their structural characteristics remain poorly understood. The mechanisms regulating mPR functions and their trafficking to the cell surface have received little attention and have not been systematically reviewed. This paper summarizes some structural aspects of mPRs, including the ligand binding pocket of mPRα recently derived from homology modeling with AdipoRs, and the proposed topology of mPRs from the preponderance of positively charged amino acid residues in their intracellular domains. The mechanisms of trafficking membrane receptors to the cell surface are discussed, including the amino acid motifs involved with their export to the cell surface, the roles of adaptor proteins, and post-translational glycosylation and palmitoylation modifications that promote cell surface expression and retention. Evidence for similar mechanisms regulating the expression and functions of mPRs on the cell surface is discussed, including the identification of potential export motifs on mPRα required for its trafficking to the cell membrane. Collectively, these results have identified several potential mechanisms regulating the expression and functions of mPRs on the cell membrane for further investigation.
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Affiliation(s)
- Peter Thomas
- University of Texas at Austin Marine Science Institute, 750 Channel View Drive, Port Aransas, TX 78373, USA.
| | - Yefei Pang
- University of Texas at Austin Marine Science Institute, 750 Channel View Drive, Port Aransas, TX 78373, USA
| | - Jan Kelder
- Theoretical & Computational Chemistry, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
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14
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Van Wynendaele M, Thieffry C, Samain L, Pierreux CE, Tyteca D, Marbaix E, Henriet P. Effects of estradiol, progesterone or cAMP on expression of PGRMC1 and progesterone receptor in a xenograft model of human endometrium and in endometrial cell culture. Steroids 2023; 198:109284. [PMID: 37487815 DOI: 10.1016/j.steroids.2023.109284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
Estradiol and progesterone are key regulators of the menstrual cycle. In the human endometrium, progesterone induces morphological changes required for blastocyst implantation. Dysregulated response to progesterone can lead to endometrial pathologies including uterine bleeding and endometriosis. Besides the canonical nuclear progesterone receptor (encoded by the PGR gene), alternative response pathways include Progesterone Receptor Membrane Component 1 (PGRMC1), suspected to be involved in pathogenesis of endometrial diseases. We previously reported the spatiotemporal profile of PGRMC1 expression in the human endometrium along the menstrual cycle, highlighting progressive increase and decrease during the proliferative and secretory phases, respectively. Here we directly addressed its regulation by estradiol and progesterone, with systematic comparison with regulation of PGR expression. We found a direct correlation between expression of both genes during the proliferative and secretory phases in the cycling endometrium, but not during the menstrual phase. In a xenograft model mimicking the cycle phases, estradiol significantly increased and progesterone significantly decreased PGR expression but changes were not significant for PGRMC1. Finally, we did not find any significant effect of the ovarian steroids on expression of PGR or PGRMC1 in primary culture of endometrial stromal cells, except for a small increase in PGR expression by estradiol. Altogether, our experiments do not allow a major advance in our understanding of the mechanisms of cyclic variation of PGRMC1 expression, in particular regarding potential regulation by the ovarian steroids.
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Affiliation(s)
- Marie Van Wynendaele
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium.
| | - Charlotte Thieffry
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium
| | - Lucie Samain
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium
| | - Christophe E Pierreux
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium.
| | - Donatienne Tyteca
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium.
| | - Etienne Marbaix
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; Pathology Department, Cliniques Universitaires Saint-Luc, B-1200 Brussels, Belgium.
| | - Patrick Henriet
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium.
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15
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Asady B, Sampels V, Romano JD, Levitskaya J, Lige B, Khare P, Le A, Coppens I. Function and regulation of a steroidogenic CYP450 enzyme in the mitochondrion of Toxoplasma gondii. PLoS Pathog 2023; 19:e1011566. [PMID: 37651449 PMCID: PMC10499268 DOI: 10.1371/journal.ppat.1011566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 09/13/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
As an obligate intracellular parasite, Toxoplasma gondii must import essential nutrients from the host cell into the parasitophorous vacuole. We previously reported that the parasite scavenges cholesterol from host endocytic organelles for incorporation into membranes and storage as cholesteryl esters in lipid droplets. In this study, we have investigated whether Toxoplasma utilizes cholesterol as a precursor for the synthesis of metabolites, such as steroids. In mammalian cells, steroidogenesis occurs in mitochondria and involves membrane-bound type I cytochrome P450 oxidases that are activated through interaction with heme-binding proteins containing a cytochrome b5 domain, such as members of the membrane-associated progesterone receptor (MAPR) family. Our LC-MS targeted lipidomics detect selective classes of hormone steroids in Toxoplasma, with a predominance for anti-inflammatory hydroxypregnenolone species, deoxycorticosterone and dehydroepiandrosterone. The genome of Toxoplasma contains homologs encoding a single type I CYP450 enzyme (we named TgCYP450mt) and a single MAPR (we named TgMAPR). We showed that TgMAPR is a hemoprotein with conserved residues in a heme-binding cytochrome b5 domain. Both TgCYP450 and TgMAPR localize to the mitochondrion and show interactions in in situ proximity ligation assays. Genetic ablation of cyp450mt is not tolerated by Toxoplasma; we therefore engineered a conditional knockout strain and showed that iΔTgCYP450mt parasites exhibit growth impairment in cultured cells. Parasite strains deficient for mapr could be generated; however, ΔTgMAPR parasites suffer from poor global fitness, loss of plasma membrane integrity, aberrant mitochondrial cristae, and an abnormally long S-phase in their cell cycle. Compared to wild-type parasites, iΔTgCYP450mt and ΔTgMAPR lost virulence in mice and metabolomics studies reveal that both mutants have reduced levels of steroids. These observations point to a steroidogenic pathway operational in the mitochondrion of a protozoan that involves an evolutionary conserved TgCYP450mt enzyme and its binding partner TgMAPR.
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Affiliation(s)
- Beejan Asady
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Vera Sampels
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Julia D. Romano
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Jelena Levitskaya
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Bao Lige
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Pratik Khare
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Anne Le
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Isabelle Coppens
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
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16
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Yakin K, Hela F, Oktem O. Progesterone signaling in the regulation of luteal steroidogenesis. Mol Hum Reprod 2023; 29:gaad022. [PMID: 37289566 PMCID: PMC10631818 DOI: 10.1093/molehr/gaad022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/23/2023] [Indexed: 06/10/2023] Open
Abstract
The corpus luteum is the major source of progesterone, the essential hormone for female reproductive function. While progesterone activity has been the subject of extensive research for decades, characterization of non-canonical progesterone receptor/signaling pathways provided a new perspective for understanding the complex signal transduction mechanisms exploited by the progesterone hormone. Deciphering these mechanisms has significant implications in the management of luteal phase disorders and early pregnancy complications. The purpose of this review is to highlight the complex mechanisms through which progesterone-induced signaling mediates luteal granulosa cell activity in the corpus luteum. Here, we review the literature and discuss the up-to-date evidence on how paracrine and autocrine effects of progesterone regulate luteal steroidogenic activity. We also review the limitations of the published data and highlight future research priorities.
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Affiliation(s)
- Kayhan Yakin
- Graduate School of Health Sciences, Koç University, Istanbul, Turkey
- School of Medicine, Department of Obstetrics and Gynecology, Koç University, Istanbul, Turkey
| | - Francesko Hela
- Graduate School of Health Sciences, Koç University, Istanbul, Turkey
- Harvard Medical School, Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, MA, USA
| | - Ozgur Oktem
- Graduate School of Health Sciences, Koç University, Istanbul, Turkey
- School of Medicine, Department of Obstetrics and Gynecology, Koç University, Istanbul, Turkey
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17
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Mullari M, Fossat N, Skotte NH, Asenjo-Martinez A, Humphreys DT, Bukh J, Kirkeby A, Scheel TKH, Nielsen ML. Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington's disease. Nat Commun 2023; 14:4348. [PMID: 37468457 DOI: 10.1038/s41467-023-39936-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/30/2023] [Indexed: 07/21/2023] Open
Abstract
RNA-binding proteins (RBPs) are key players regulating RNA processing and are associated with disorders ranging from cancer to neurodegeneration. Here, we present a proteomics workflow for large-scale identification of RBPs and their RNA-binding regions in the mammalian brain identifying 526 RBPs. Analysing brain tissue from males of the Huntington's disease (HD) R6/2 mouse model uncovered differential RNA-binding of the alternative splicing regulator RBM5. Combining several omics workflows, we show that RBM5 binds differentially to transcripts enriched in pathways of neurodegeneration in R6/2 brain tissue. We further find these transcripts to undergo changes in splicing and demonstrate that RBM5 directly regulates these changes in human neurons derived from embryonic stem cells. Finally, we reveal that RBM5 interacts differently with several known huntingtin interactors and components of huntingtin aggregates. Collectively, we demonstrate the applicability of our method for capturing RNA interactor dynamics in the contexts of tissue and disease.
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Affiliation(s)
- Meeli Mullari
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Nicolas Fossat
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- CO-HEP, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark
| | - Niels H Skotte
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Asenjo-Martinez
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
| | - David T Humphreys
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- CO-HEP, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark
| | - Agnete Kirkeby
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
- Wallenberg Center for Molecular Medicine (WCMM) and Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Troels K H Scheel
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- CO-HEP, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Michael L Nielsen
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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18
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Song Z, Xiong H, Meng X, Ma Q, Wei Y, Li Y, Liu J, Liang M, Xu H. Dietary Cholesterol Supplementation Inhibits the Steroid Biosynthesis but Does Not Affect the Cholesterol Transport in Two Marine Teleosts: A Hepatic Transcriptome Study. AQUACULTURE NUTRITION 2023; 2023:2308669. [PMID: 37312679 PMCID: PMC10260315 DOI: 10.1155/2023/2308669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/09/2023] [Accepted: 05/26/2023] [Indexed: 06/15/2023]
Abstract
Cholesterol has been used as additive in fish feeds due to the reduced use of fish meal and fish oil. In order to evaluate the effects of dietary cholesterol supplementation (D-CHO-S) on fish physiology, a liver transcriptome analysis was performed following a feeding experiment on turbot and tiger puffer with different levels of dietary cholesterol. The control diet contained 30% fish meal (0% fish oil) without cholesterol supplementation, while the treatment diet was supplemented with 1.0% cholesterol (CHO-1.0). A total of 722 and 581 differentially expressed genes (DEG) between the dietary groups were observed in turbot and tiger puffer, respectively. These DEG were primarily enriched in signaling pathways related to steroid synthesis and lipid metabolism. In general, D-CHO-S downregulated the steroid synthesis in both turbot and tiger puffer. Msmo1, lss, dhcr24, and nsdhl might play key roles in the steroid synthesis in these two fish species. Gene expressions related to cholesterol transport (npc1l1, abca1, abcg1, abcg2, abcg5, abcg8, abcb11a, and abcb11b) in the liver and intestine were also extensively investigated by qRT-PCR. However, the results suggest that D-CHO-S rarely affected the cholesterol transport in both species. The protein-protein interaction (PPI) network constructed on steroid biosynthesis-related DEG showed that in turbot, Msmo1, Lss, Nsdhl, Ebp, Hsd17b7, Fdft1, and Dhcr7 had high intermediary centrality in the dietary regulation of steroid synthesis. In conclusion, in both turbot and tiger puffer, the supplementation of dietary cholesterol inhibits the steroid metabolism but does not affect the cholesterol transport.
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Affiliation(s)
- Ziling Song
- College of Fisheries and Life Sciences, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, China
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Haiyan Xiong
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Xiaoxue Meng
- College of Fisheries and Life Sciences, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, China
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Qiang Ma
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Yuliang Wei
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Yanlu Li
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Jian Liu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Mengqing Liang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Houguo Xu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
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19
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Lizama BN, Kahle J, Catalano SM, Caggiano AO, Grundman M, Hamby ME. Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases. Int J Mol Sci 2023; 24:ijms24076251. [PMID: 37047224 PMCID: PMC10093856 DOI: 10.3390/ijms24076251] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/18/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration.
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Affiliation(s)
| | | | | | | | - Michael Grundman
- Global R&D Partners, LLC., San Diego, CA 92130, USA
- Department of Neurosciences, University of California, San Diego, CA 92093, USA
| | - Mary E. Hamby
- Cognition Therapeutics, Inc., Pittsburgh, PA 15203, USA
- Correspondence:
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20
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Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases. Int J Mol Sci 2023; 24:ijms24054908. [PMID: 36902339 PMCID: PMC10002949 DOI: 10.3390/ijms24054908] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Sphingolipids containing acyl residues that are hydroxylated at C-2 are found in most, if not all, eukaryotes and certain bacteria. 2-hydroxylated sphingolipids are present in many organs and cell types, though they are especially abundant in myelin and skin. The enzyme fatty acid 2-hydroxylase (FA2H) is involved in the synthesis of many but not all 2-hydroxylated sphingolipids. Deficiency in FA2H causes a neurodegenerative disease known as hereditary spastic paraplegia 35 (HSP35/SPG35) or fatty acid hydroxylase-associated neurodegeneration (FAHN). FA2H likely also plays a role in other diseases. A low expression level of FA2H correlates with a poor prognosis in many cancers. This review presents an updated overview of the metabolism and function of 2-hydroxylated sphingolipids and the FA2H enzyme under physiological conditions and in diseases.
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Obi CD, Dailey HA, Jami-Alahmadi Y, Wohlschlegel JA, Medlock AE. Proteomic Analysis of Ferrochelatase Interactome in Erythroid and Non-Erythroid Cells. Life (Basel) 2023; 13:577. [PMID: 36836934 PMCID: PMC9958551 DOI: 10.3390/life13020577] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/24/2023] [Accepted: 02/13/2023] [Indexed: 02/22/2023] Open
Abstract
Heme is an essential cofactor for multiple cellular processes in most organisms. In developing erythroid cells, the demand for heme synthesis is high, but is significantly lower in non-erythroid cells. While the biosynthesis of heme in metazoans is well understood, the tissue-specific regulation of the pathway is less explored. To better understand this, we analyzed the mitochondrial heme metabolon in erythroid and non-erythroid cell lines from the perspective of ferrochelatase (FECH), the terminal enzyme in the heme biosynthetic pathway. Affinity purification of FLAG-tagged-FECH, together with mass spectrometric analysis, was carried out to identify putative protein partners in human and murine cell lines. Proteins involved in the heme biosynthetic process and mitochondrial organization were identified as the core components of the FECH interactome. Interestingly, in non-erythroid cell lines, the FECH interactome is highly enriched with proteins associated with the tricarboxylic acid (TCA) cycle. Overall, our study shows that the mitochondrial heme metabolon in erythroid and non-erythroid cells has similarities and differences, and suggests new roles for the mitochondrial heme metabolon and heme in regulating metabolic flux and key cellular processes.
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Affiliation(s)
- Chibuike David Obi
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - Harry A. Dailey
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
- Department of Microbiology, University of Georgia, Athens, GA 30602, USA
| | - Yasaman Jami-Alahmadi
- Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - James A. Wohlschlegel
- Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Amy E. Medlock
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
- Augusta University/University of Georgia Medical Partnership, Athens, GA 30606, USA
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McGuire MR, Espenshade PJ. PGRMC1: An enigmatic heme-binding protein. Pharmacol Ther 2023; 241:108326. [PMID: 36463977 PMCID: PMC9839567 DOI: 10.1016/j.pharmthera.2022.108326] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/22/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
Progesterone Receptor Membrane Component 1 (PGRMC1) is a heme-binding protein that has been implicated in a wide range of cell and tissue functions, including cytochromes P450 activity, heme homeostasis, cancer, female reproduction, and protein quality control. Despite an extensive body of literature, a relative lack of mechanistic insight means that how PGRMC1 functions in these different aspects of biology is largely unknown. This review provides an overview of the PGRMC1 literature, highlighting what information is rigorously supported by experimental evidence and where additional investigation is warranted. The central role of PGRMC1 in supporting cytochrome P450 activity is discussed at length. Building on existing models of PGRMC1 function, a speculative model is proposed using the reviewed literature in which PGRMC1 functions as a heme chaperone to shuttle heme from its site of synthesis in the mitochondrion to other subcellular compartments. By spotlighting knowledge gaps, this review will motivate investigators to better understand this enigmatic protein.
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Affiliation(s)
- Meredith R McGuire
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter J Espenshade
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Physiology 107B, Baltimore, MD 21205, USA.
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23
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Abaffy T, Lu HY, Matsunami H. Sex steroid hormone synthesis, metabolism, and the effects on the mammalian olfactory system. Cell Tissue Res 2023; 391:19-42. [PMID: 36401093 PMCID: PMC9676892 DOI: 10.1007/s00441-022-03707-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022]
Abstract
Sex steroid hormones influence olfactory-mediated social behaviors, and it is generally hypothesized that these effects result from circulating hormones and/or neurosteroids synthesized in the brain. However, it is unclear whether sex steroid hormones are synthesized in the olfactory epithelium or the olfactory bulb, and if they can modulate the activity of the olfactory sensory neurons. Here, we review important discoveries related to the metabolism of sex steroids in the mouse olfactory epithelium and olfactory bulb, along with potential areas of future research. We summarize current knowledge regarding the expression, neuroanatomical distribution, and biological activity of the steroidogenic enzymes, sex steroid receptors, and proteins that are important to the metabolism of these hormones and reflect on their potential to influence early olfactory processing. We also review evidence related to the effects of sex steroid hormones on the development and activity of olfactory sensory neurons. By better understanding how these hormones are metabolized and how they act both at the periphery and olfactory bulb level, we can better appreciate the complexity of the olfactory system and discover potential similarities and differences in early olfactory processing between sexes.
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Affiliation(s)
- Tatjana Abaffy
- Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710 USA
| | - Hsiu-Yi Lu
- Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710 USA
| | - Hiroaki Matsunami
- Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710 USA
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24
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Zhao S, Hughes AL, Espenshade PJ. Fission yeast Dap1 heme iron-coordinating residue Y83 is required for cytochromes P450 function. MICROPUBLICATION BIOLOGY 2022; 2022:10.17912/micropub.biology.000631. [PMID: 36090151 PMCID: PMC9449707 DOI: 10.17912/micropub.biology.000631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 11/28/2022]
Abstract
Fission yeast Dap1 is a heme binding protein required for cytochromes P450 activity. Here, we tested whether Dap1 axial coordination of heme iron is required for its role in the function of the cytochrome P450 enzymes, Erg5 and Erg11. Two different dap1 mutants predicted to alter iron coordination failed to rescue growth on cobalt chloride containing medium which requires Erg5 and Erg11. In addition, deletion of dap1 + did not affect expression of Erg5 or Erg11. PGRMC1, a mammalian Dap1 homolog, does not require heme binding to bind and stabilize cytochromes P450. These experiments highlight important functional differences between these conserved proteins.
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Affiliation(s)
- Shan Zhao
- Johns Hopkins University School of Medicine, USA
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25
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Velázquez Hernández DM, Vázquez-Martínez ER, Camacho-Arroyo I. The role of progesterone receptor membrane component (PGRMC) in the endometrium. Steroids 2022; 184:109040. [PMID: 35526781 DOI: 10.1016/j.steroids.2022.109040] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/25/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022]
Abstract
PGRMC is a non-classical receptor that mediates the non-genomic responses to progesterone and is distributed in different subcellular compartments. PGRMC belongs to the membrane-associated progesterone receptor (MAPR) family. Two PGRMC subtypes (PGRMC1 and PGRMC2) have been characterized, and both are expressed in the human endometrium. PGRMC expression is differentially regulated during the menstrual cycle in the human endometrium. Although PGRMC1 is predominantly expressed in the proliferative phase and PGRMC2 in the secretory phase, this expression changes in pathologies such as endometriosis, in which PGRMC2 expression considerably decreases, promoting progesterone resistance. In endometrial cancer, PGRMC1 is overexpressed, its activation induces tumors growth, and confers chemoresistance in the presence of progesterone. Thus, PGRMCs play a key role in progesterone actions in the endometrium.
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Affiliation(s)
- Dora Maria Velázquez Hernández
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Edgar Ricardo Vázquez-Martínez
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Ignacio Camacho-Arroyo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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Khojasteh SC, Argikar UA, Cho S, Crouch R, Heck CJS, Johnson KM, Kalgutkar AS, King L, Maw HH, Seneviratne HK, Wang S, Wei C, Zhang D, Jackson KD. Biotransformation Novel Advances - 2021 year in review. Drug Metab Rev 2022; 54:207-245. [PMID: 35815654 DOI: 10.1080/03602532.2022.2097253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).
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Affiliation(s)
- S Cyrus Khojasteh
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS412a, South San Francisco, CA, 94080, USA
| | - Upendra A Argikar
- Non-clinical Development, Bill & Melinda Gates Medical Research Institute, Cambridge, MA 02139, USA
| | - Sungjoon Cho
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS412a, South San Francisco, CA, 94080, USA
| | - Rachel Crouch
- Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy and Health Sciences, Nashville, TN, 37203, USA
| | - Carley J S Heck
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Eastern Point Road, Groton, Connecticut, USA
| | - Kevin M Johnson
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS412a, South San Francisco, CA, 94080, USA
| | - Amit S Kalgutkar
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Cambridge, MA 02139, USA
| | - Lloyd King
- Quantitative Drug Discovery, UCB Biopharma UK, 216 Bath Road, Slough, SL1 3WE, UK
| | - Hlaing Holly Maw
- Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 06877, USA
| | - Herana Kamal Seneviratne
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Shuai Wang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS412a, South San Francisco, CA, 94080, USA
| | - Cong Wei
- Drug Metabolism & Pharmacokinetics, Biogen Inc., Cambridge, MA, 02142, USA
| | - Donglu Zhang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS412a, South San Francisco, CA, 94080, USA
| | - Klarissa D Jackson
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA
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27
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Abstract
Progesterone receptor membrane component (PGRMC) proteins play important roles in tumor growth, progression, and chemoresistance, of which PGRMC1 is the best characterized. The ancestral member predates the evolution of metazoans, so it is perhaps not surprising that many of the purported actions of PGRMC proteins are rooted in fundamental metabolic processes such as proliferation, apoptosis, and DNA damage responses. Despite mediating some of the actions of progesterone (P4) and being fundamentally required for female fertility, PGRMC1 and PGRMC2 are broadly expressed in most tissues. As such, these proteins likely have both progesterone-dependent and progesterone-independent functions. It has been proposed that PGRMC1 acquired the ability to mediate P4 actions over evolutionary time through acquisition of its cytochrome b5-like heme/sterol-binding domain. Diverse reproductive and nonreproductive diseases associate with altered PGRMC1 expression, epigenetic regulation, or gene silencing mechanisms, some of which include polycystic ovarian disease, premature ovarian insufficiency, endometriosis, Alzheimer disease, and cancer. Although many studies have been completed using transformed cell lines in culture or in xenograft tumor approaches, recently developed transgenic model organisms are offering new insights in the physiological actions of PGRMC proteins, as well as pathophysiological and oncogenic consequences when PGRMC expression is altered. The purpose of this mini-review is to provide an overview of PGRMC proteins in cancer and to offer discussion of where this field must go to solidify PGRMC proteins as central contributors to the oncogenic process.
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Affiliation(s)
- James K Pru
- Correspondence: James K. Pru, PhD, Program in Reproductive Biology, Department of Animal Science, University of Wyoming, Laramie, WY, USA.
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28
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Possible Involvement of miR-98 in the Regulation of PGRMC1 During Decidualization. REPRODUCTIVE MEDICINE 2022. [DOI: 10.3390/reprodmed3020015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Human endometrial stromal cells (ESCs) differentiate into decidual cells for embryo implantation during the mid-secretory phase of the menstrual cycle. Decidualization is characterized by enhanced production of insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL) by ESCs and their morphological transformation into polygonal cells. Progesterone (P4) receptor membrane component 1 (PGRMC1) is a member of a P4-binding complex implicated in function in female reproduction. In this study, we explored the mechanisms that regulate PGRMC1 during decidualization of human ESCs. Immunohistochemical analysis of endometrial samples showed that PGRMC1 was expressed in endometrial glandular and luminal epithelial cells and stromal cells throughout the menstrual cycle; however, the protein level in stroma was reduced in the secretory phase. Incubation of ESCs with dibutyryl (db)-cAMP and P4 in vitro, which induces decidualization, decreased the PGRMC1 protein abundance. Further, treatment with a PGRMC1-targeting siRNA or PGRMC1 inhibitor (AG-205) promoted mRNA expression of the db-cAMP/P4- and db-cAMP-induced decidual markers IGFBP1 and PRL. Moreover, the microRNA miR-98, a potential repressor of PGRMC1, was upregulated during decidualization, and transfection of ESCs with a miR-98 mimic decreased the PGRMC1 protein level. These findings suggest that miR-98-mediated downregulation of endometrial PGRMC1 may promote decidualization for the establishment of pregnancy.
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29
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Zhao J, Zhang H, Fan X, Yu X, Huai J. Lipid Dyshomeostasis and Inherited Cerebellar Ataxia. Mol Neurobiol 2022; 59:3800-3828. [PMID: 35420383 PMCID: PMC9148275 DOI: 10.1007/s12035-022-02826-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/01/2022] [Indexed: 12/04/2022]
Abstract
Cerebellar ataxia is a form of ataxia that originates from dysfunction of the cerebellum, but may involve additional neurological tissues. Its clinical symptoms are mainly characterized by the absence of voluntary muscle coordination and loss of control of movement with varying manifestations due to differences in severity, in the site of cerebellar damage and in the involvement of extracerebellar tissues. Cerebellar ataxia may be sporadic, acquired, and hereditary. Hereditary ataxia accounts for the majority of cases. Hereditary ataxia has been tentatively divided into several subtypes by scientists in the field, and nearly all of them remain incurable. This is mainly because the detailed mechanisms of these cerebellar disorders are incompletely understood. To precisely diagnose and treat these diseases, studies on their molecular mechanisms have been conducted extensively in the past. Accumulating evidence has demonstrated that some common pathogenic mechanisms exist within each subtype of inherited ataxia. However, no reports have indicated whether there is a common mechanism among the different subtypes of inherited cerebellar ataxia. In this review, we summarize the available references and databases on neurological disorders characterized by cerebellar ataxia and show that a subset of genes involved in lipid homeostasis form a new group that may cause ataxic disorders through a common mechanism. This common signaling pathway can provide a valuable reference for future diagnosis and treatment of ataxic disorders.
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Affiliation(s)
- Jin Zhao
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Huan Zhang
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xueyu Fan
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xue Yu
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jisen Huai
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China.
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China.
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30
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Thomas P. Membrane Progesterone Receptors (mPRs, PAQRs): Review of Structural and Signaling Characteristics. Cells 2022; 11:cells11111785. [PMID: 35681480 PMCID: PMC9179843 DOI: 10.3390/cells11111785] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 02/05/2023] Open
Abstract
The role of membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor (PAQR) family, in mediating rapid, nongenomic (non-classical) progestogen actions has been extensively studied since their identification 20 years ago. Although the mPRs have been implicated in progestogen regulation of numerous reproductive and non-reproductive functions in vertebrates, several critical aspects of their structure and signaling functions have been unresolved until recently and remain the subject of considerable debate. This paper briefly reviews recent developments in our understanding of the structure and functional characteristics of mPRs. The proposed membrane topology of mPRα, the structure of its ligand-binding site, and the binding affinities of steroids were predicted from homology modeling based on the structures of other PAQRs, adiponectin receptors, and confirmed by mutational analysis and ligand-binding assays. Extensive data demonstrating that mPR-dependent progestogen regulation of intracellular signaling through mPRs is mediated by activation of G proteins are reviewed. Close association of mPRα with progesterone membrane receptor component 1 (PGRMC1), its role as an adaptor protein to mediate cell-surface expression of mPRα and mPRα-dependent progestogen signaling has been demonstrated in several vertebrate models. In addition, evidence is presented that mPRs can regulate the activity of other hormone receptors.
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Affiliation(s)
- Peter Thomas
- Marine Science Institute, The University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX 78373, USA
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31
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Peluso JJ. Progesterone Signaling and Mammalian Ovarian Follicle Growth Mediated by Progesterone Receptor Membrane Component Family Members. Cells 2022; 11:1632. [PMID: 35626669 PMCID: PMC9139379 DOI: 10.3390/cells11101632] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 02/01/2023] Open
Abstract
How progesterone influences ovarian follicle growth is a difficult question to answer because ovarian cells synthesize progesterone and express not only the classic nuclear progesterone receptor but also members of the progestin and adipoQ receptor family and the progesterone receptor membrane component (PGRMC) family. Which type of progestin receptor is expressed depends on the ovarian cell type as well as the stage of the estrous/menstrual cycle. Given the complex nature of the mammalian ovary, this review will focus on progesterone signaling that is transduced by PGRMC1 and PGRMC2 specifically as it relates to ovarian follicle growth. PGRMC1 was identified as a progesterone binding protein cloned from porcine liver in 1996 and detected in the mammalian ovary in 2005. Subsequent studies focused on PGRMC family members as regulators of granulosa cell proliferation and survival, two physiological processes required for follicle development. This review will present evidence that demonstrates a causal relationship between PGRMC family members and the promotion of ovarian follicle growth. The mechanisms through which PGRMC-dependent signaling regulates granulosa cell proliferation and viability will also be discussed in order to provide a more complete understanding of our current concept of how progesterone regulates ovarian follicle growth.
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Affiliation(s)
- John J. Peluso
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA;
- Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, CT 06030, USA
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Effect of Steroid Hormones, Prostaglandins (E2 and F2α), Oxytocin, and Tumor Necrosis Factor Alpha on Membrane Progesterone (P4) Receptors Gene Expression in Bovine Myometrial Cells. Animals (Basel) 2022; 12:ani12040519. [PMID: 35203226 PMCID: PMC8868417 DOI: 10.3390/ani12040519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/11/2022] [Accepted: 02/16/2022] [Indexed: 02/04/2023] Open
Abstract
Myometrium tissue shows the expression of non-genomic membrane progesterone (P4) receptors, such as progesterone receptor membrane components (PGRMC) 1 and 2 and membrane progestin receptors (mPR) alpha (mPRα), beta (mPRβ), and gamma (mPRγ). Their variable expression in the bovine uterus during the estrous cycle and early pregnancy suggests that ovarian steroids and luteotropic and/or luteolytic factors may regulate the expression of these receptors in the myometrium. Therefore, this study aimed to examine the effect of P4, estradiol (E2), P4 with E2, prostaglandins (PG) E2 and F2α, oxytocin (OT), and tumor necrosis factor α (TNFα) on the gene expression of PGRMC1, PGRMC2, serpine-1 mRNA-binding protein (SERBP1), and mPRα, mPRβ, and mPRγ in bovine myometrial cells from days 6 to 10 and 11 to 16 of the estrous cycle. The PGE2 concentration and mRNA expression were determined by EIA and real-time PCR, respectively. The data indicated that P4 and E2 can affect the mRNA expression of all studied receptors and SERPB1. However, PGE2, OT, and TNFα could only modulate the expression of PGRMC1, PGRMC2, and SERPB1, respectively. Steroids/factors changed the expression of PGRMC and mPR genes depending on the dose, the stage of the estrous cycle, and the types of receptors. This suggests that the local hormonal milieu may influence the activity of these receptors and P4 action in myometrial cells during the estrous cycle.
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33
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He Y, Dong XH, Zhu Q, Xu YL, Chen ML, Liu Z. Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo. Mil Med Res 2022; 9:9. [PMID: 35152910 PMCID: PMC8842919 DOI: 10.1186/s40779-022-00369-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/28/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Ultrasound-triggered microbubble destruction (UTMD) is a widely used noninvasive technology in both military and civilian medicine, which could enhance radiosensitivity of various tumors. However, little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism. This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy. METHODS GL261, U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation (IR) or IR plus UTMD. Autophagy was observed by confocal microscopy and transmission electron microscopy. Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1 (PGRMC1), light chain 3 beta 2 (LC3B2) and sequestosome 1 (SQSTM1/p62) levels. Lentiviral vectors or siRNAs transfection, and fluorescent probes staining were used to explore the underlying mechanism. RESULTS UTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo (P < 0.01). UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells. Suppression of autophagy by 3-methyladenine, bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells (P < 0.05). Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression (P > 0.05). Furthermore, UTMD inhibited PGRMC1 expression and binding with LC3B2 in IR-exposed glioblastoma cells (P < 0.01). PGRMC1 inhibitor AG-205 or PGRMC1 siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells, thereby promoting UTMD-mediated radiosensitization (P < 0.05). Moreover, PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation, subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells. Finally, compared with IR plus UTMD group, PGRMC1 overexpression significantly increased tumor size [(3.8 ± 1.1) mm2 vs. (8.0 ± 1.9) mm2, P < 0.05] and decreased survival time [(67.2 ± 2.6) d vs. (40.0 ± 1.2) d, P = 0.0026] in glioblastoma-bearing mice. CONCLUSION UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.
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Affiliation(s)
- Ying He
- Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Xun-Hu Dong
- Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Institute of Toxicology, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qiong Zhu
- Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Ya-Li Xu
- Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Ming-Liang Chen
- Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China. .,Institute of Toxicology, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China. .,Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Zheng Liu
- Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China.
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González AM, Venegas M, Barahona S, Gómez M, Gutiérrez MS, Sepúlveda D, Baeza M, Cifuentes V, Alcaíno J. Damage response protein 1 (Dap1) functions in the synthesis of carotenoids and sterols in Xanthophyllomyces dendrorhous. J Lipid Res 2022; 63:100175. [PMID: 35120994 PMCID: PMC8953664 DOI: 10.1016/j.jlr.2022.100175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open
Abstract
Cytochrome P450s (P450s) are heme-containing proteins involved in several cellular functions, including biosynthesis of steroidal hormones, detoxification of xenobiotic compounds, among others. Damage response protein 1 (Dap1) has been described as a positive regulator of P450s through protein-protein interactions in organisms such as Schizosaccharomyces pombe. Three P450s in the carotenogenic yeast Xanthophyllomyces dendrorhous have thus far been characterized: Cyp51 and Cyp61, which are involved in ergosterol biosynthesis, and CrtS (astaxanthin synthase), which is involved in biosynthesis of the carotenoid astaxanthin. In this work, we describe the X. dendrorhous DAP1 gene, deletion of which affected yeast pigmentation by decreasing the astaxanthin fraction and increasing the β-carotene (a substrate of CrtS) fraction, which is consistent with the known role of CrtS. We found that the proportion of ergosterol was also decreased in the Δdap1 mutant. However, even though the fractions of the end products of these two pathways (the synthesis of carotenoids and sterols) were decreased in the Δdap1 mutant, the transcript levels of genes from the P450 systems involved were higher than those in the wild-type strain. We demonstrate that Dap1 coimmunoprecipitates with these three P450s, suggesting that Dap1 interacts with these three proteins. We propose that Dap1 regulates the synthesis of astaxanthin and ergosterol in X. dendrorhous, probably by regulating the P450s involved in both biosynthetic pathways at the protein level. This work suggests a new role for Dap1 in the regulation of carotenoid biosynthesis in X. dendrorhous.
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Affiliation(s)
- Ana-María González
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Maximiliano Venegas
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Salvador Barahona
- Centro de Biotecnología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Melissa Gómez
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - María-Soledad Gutiérrez
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Dionisia Sepúlveda
- Centro de Biotecnología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Marcelo Baeza
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Centro de Biotecnología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Víctor Cifuentes
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Centro de Biotecnología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Jennifer Alcaíno
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile; Centro de Biotecnología, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
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The PGRMC1 Antagonist AG-205 Inhibits Synthesis of Galactosylceramide and Sulfatide. Cells 2021; 10:cells10123520. [PMID: 34944026 PMCID: PMC8700550 DOI: 10.3390/cells10123520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 02/05/2023] Open
Abstract
Sulfatide synthesis in the human renal cancer cell line SMKT-R3 was strongly inhibited in the presence of low µM concentrations of AG-205, a progesterone receptor membrane component 1 (PGRMC1) antagonist. This was also the case in Chinese hamster ovary (CHO) cells stably transfected with UDP-galactose: ceramide galactosyltransferase and cerebroside sulfotransferase, the two enzymes required for sulfatide synthesis. In CHO cells synthesizing galactosylceramide but not sulfatide, galactosylceramide was also strongly reduced, suggesting an effect at the level of galactolipid synthesis. Notably, AG-205 inhibited galactosylceramide synthesis to a similar extent in wild type CHO cells and cells that lack PGRMC1 and/or PGRMC2. In vitro enzyme activity assays showed that AG-205 is an inhibitor of UDP-galactose: ceramide galactosyltransferase, but not cerebroside sulfotransferase. This study shows that PGRMC1 is only one of several targets of AG-205 and should be used with caution, especially in studies using cells synthesizing galactosylceramide and sulfatide.
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Solairaja S, Ramalingam S, Dunna NR, Venkatabalasubramanian S. Progesterone Receptor Membrane Component 1 and Its Accomplice: Emerging Therapeutic Targets in Lung Cancer. Endocr Metab Immune Disord Drug Targets 2021; 22:601-611. [PMID: 34847852 DOI: 10.2174/1871530321666211130145542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/13/2021] [Accepted: 10/28/2021] [Indexed: 12/24/2022]
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is a trans-membrane evolutionarily conserved protein with a cytochrome b5 like heme/steroid binding domain. PGRMC1 clinical levels are strongly suggested to correlate with poor patient survival and lung cancer prognosis. PGRMC1 has been reported to possess pleiotropic functions, such as participating in cellular and membrane trafficking, steroid hormone signaling, cholesterol metabolism and steroidogenesis, glycolysis and mitochondrial energy metabolism, heme transport and homeostasis, neuronal movement and synaptic function, autophagy, anti-apoptosis, stem cell survival and the list is still expanding. PGRMC1 mediates its pleiotropic functions through its ability to interact with multiple binding partners, such as epidermal growth factor receptor (EGFR), sterol regulatory element binding protein cleavage activating protein (SCAP), insulin induced gene-1 protein (Insig-1), heme binding proteins (hepcidin, ferrochelatase and cyp450 members), plasminogen activator inhibitor 1 RNA binding protein (PAIR-BP1). In this review, we provide a comprehensive overview of PGRMC1 and its associated pleiotropic functions that are indispensable for lung cancer promotion and progression, suggesting it as a prospective therapeutic target for intervention. Notably, we have compiled and reported various preclinical studies wherein prospective agonists and antagonists had been tested against PGRMC1 expressing cancer cell lines, suggesting it as a prospective therapeutic target for cancer intervention.
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Affiliation(s)
- Solaipriya Solairaja
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur Campus, Tamil Nadu, Chennai-603203. India
| | - Satish Ramalingam
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur Campus, Tamil Nadu, Chennai-603203. India
| | - Nageswara Rao Dunna
- Cancer Genomics Laboratory, Department of Biotechnology, School of Chemical and Biotechnology, SASTRA - Deemed University, Thanjavur 613 401. India
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Bai Y, Ludescher M, Poschmann G, Stühler K, Wyrich M, Oles J, Franken A, Rivandi M, Abramova A, Reinhardt F, Ruckhäberle E, Niederacher D, Fehm T, Cahill MA, Stamm N, Neubauer H. PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling. Cancers (Basel) 2021; 13:cancers13225635. [PMID: 34830790 PMCID: PMC8615993 DOI: 10.3390/cancers13225635] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Combined menopausal hormone therapy is associated with increased breast cancer risk in postmenopausal women. In our previous studies, progesterone receptor membrane component 1 (PGRMC1) was shown to play a role in progestins’ elicitation of enhanced proliferation of breast cancer cells. Here we describe a potential mechanism by which PGRMC1 contributes to breast cancer progression via interaction with prohibitins, inhibiting their function as transcriptional repressors. This facilitates estrogen receptor alpha (ERα) transcriptional activity and enhances oncogenic signaling upon treatment with certain progestins, including norethisterone and dydrogesterone. Our data underline the contribution of PGRMC1 to especially hormone receptor positive breast cancer pathogenesis and demonstrate the need for further studies to understand its role in cancer. Abstract In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.
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Affiliation(s)
- Yingxue Bai
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Marina Ludescher
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Gereon Poschmann
- Institute for Molecular Medicine, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany; (G.P.); (K.S.)
| | - Kai Stühler
- Institute for Molecular Medicine, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany; (G.P.); (K.S.)
- Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany
| | - Martine Wyrich
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Julia Oles
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - André Franken
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Mahdi Rivandi
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Anna Abramova
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Florian Reinhardt
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Eugen Ruckhäberle
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Dieter Niederacher
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Tanja Fehm
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
| | - Michael A. Cahill
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia;
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Canberra, ACT 2601, Australia
| | - Nadia Stamm
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
- Correspondence: (N.S.); (H.N.); Tel.: +49-211-81-06026 (H.N.)
| | - Hans Neubauer
- Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Merowingerplatz 1a, 40225 Duesseldorf, Germany; (Y.B.); (M.L.); (M.W.); (J.O.); (A.F.); (M.R.); (A.A.); (F.R.); (E.R.); (D.N.); (T.F.)
- Correspondence: (N.S.); (H.N.); Tel.: +49-211-81-06026 (H.N.)
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You JH, Lee J, Roh JL. PGRMC1-dependent lipophagy promotes ferroptosis in paclitaxel-tolerant persister cancer cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:350. [PMID: 34749765 PMCID: PMC8573965 DOI: 10.1186/s13046-021-02168-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/01/2021] [Indexed: 01/02/2023]
Abstract
Background Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. Therefore, we examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC). Methods The effects of ferroptosis inducers and PGRMC1 gene silencing/overexpression were tested on head and neck cancer (HNC) cell lines and mouse tumor xenograft models. The results were analyzed about cell viability, death, lipid ROS and iron production, mRNA/protein expression and interaction, and lipid assays. Results PCC had more free fatty acids, lipid droplets, and fatty acid oxidation (FAO) than their parental cells. PCC was highly sensitive to inhibitors of system xc− cystine/glutamate antiporter (xCT), such as erastin, sulfasalazine, and cyst(e)ine deprivation, but less sensitive to (1S,3R)-RSL3. PGRMC1 silencing in PCC reduced ferroptosis sensitivity by xCT inhibitors, and PGRMC1 overexpression in parental cells increased ferroptosis by xCT inhibitors. Lipid droplets were degraded along with autophagy induction and autophagosome formation by erastin treatment in PCC. Lipophagy was accompanied by increased tubulin detyrosination, which was increased by SIRT1 activation but decreased by SIRT1 inhibition. FAO and lipophagy were also promoted by the interaction between lipid droplets and mitochondria. Conclusion PGRMC1 expression increased FAO and ferroptosis sensitivity from in vivo mice experiments. Our data suggest that PGRMC1 promotes ferroptosis by xCT inhibition in PCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02168-2. Paclitaxel-tolerant persister cancer cells (PCC) had PGRMC1 upregulation related to increased free fatty acids, lipid droplets, and fatty acid oxidation. PGRMC1 expression substantially increased ferroptosis by xCT inhibition via lipophagy and tubulin detyrosination, whereas PGRMC1 silencing decreased ferroptosis: this suggests that PGRMC1 expression promotes ferroptosis in PCC.
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Affiliation(s)
- Ji Hyeon You
- Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, 13496, Republic of Korea
| | - Jaewang Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, 13496, Republic of Korea
| | - Jong-Lyel Roh
- Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, 13496, Republic of Korea.
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McGuire MR, Mukhopadhyay D, Myers SL, Mosher EP, Brookheart RT, Kammers K, Sehgal A, Selen ES, Wolfgang MJ, Bumpus NN, Espenshade PJ. Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism. J Biol Chem 2021; 297:101316. [PMID: 34678314 PMCID: PMC8591507 DOI: 10.1016/j.jbc.2021.101316] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 10/12/2021] [Accepted: 10/18/2021] [Indexed: 12/03/2022] Open
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein implicated in a wide range of cellular functions. We previously showed that PGRMC1 binds to cytochromes P450 in yeast and mammalian cells and supports their activity. Recently, the paralog PGRMC2 was shown to function as a heme chaperone. The extent of PGRMC1 function in cytochrome P450 biology and whether PGRMC1 is also a heme chaperone are unknown. Here, we examined the function of Pgrmc1 in mouse liver using a knockout model and found that Pgrmc1 binds and stabilizes a broad range of cytochromes P450 in a heme-independent manner. Proteomic and transcriptomic studies demonstrated that Pgrmc1 binds more than 13 cytochromes P450 and supports maintenance of cytochrome P450 protein levels posttranscriptionally. In vitro assays confirmed that Pgrmc1 KO livers exhibit reduced cytochrome P450 activity consistent with reduced enzyme levels. Mechanistic studies in cultured cells demonstrated that PGRMC1 stabilizes cytochromes P450 and that binding and stabilization do not require PGRMC1 binding to heme. Importantly, Pgrmc1-dependent stabilization of cytochromes P450 is physiologically relevant, as Pgrmc1 deletion protected mice from acetaminophen-induced liver injury. Finally, evaluation of Y113F mutant Pgrmc1, which lacks the axial heme iron-coordinating hydroxyl group, revealed that proper iron coordination is not required for heme binding, but is required for binding to ferrochelatase, the final enzyme in heme biosynthesis. PGRMC1 was recently identified as the causative mutation in X-linked isolated pediatric cataract formation. Together, these results demonstrate a heme-independent function for PGRMC1 in cytochrome P450 stability that may underlie clinical phenotypes.
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Affiliation(s)
- Meredith R McGuire
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Debaditya Mukhopadhyay
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stephanie L Myers
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Eric P Mosher
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rita T Brookheart
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kai Kammers
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alfica Sehgal
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ebru S Selen
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Namandjé N Bumpus
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Peter J Espenshade
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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Thieffry C, Van Wynendaele M, Aynaci A, Maja M, Dupuis C, Loriot A, Marbaix E, Henriet P. AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins. Biomolecules 2021; 11:1472. [PMID: 34680104 PMCID: PMC8533447 DOI: 10.3390/biom11101472] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/27/2022] Open
Abstract
An inappropriate response to progestogens in the human endometrium can result in fertility issues and jeopardize progestin-based treatments against pathologies such as endometriosis. PGRMC1 can mediate progesterone response in the breast and ovaries but its endometrial functions remain unknown. AG-205 is an alleged PGRMC1 inhibitor but its specificity was recently questioned. We added AG-205 in the cultures of two endometrial cell lines and performed a transcriptomic comparison. AG-205 significantly increased expression of genes coding enzymes of the cholesterol biosynthetic pathway or of steroidogenesis. However, these observations were not reproduced with cells transfected with siRNA against PGRMC1 or its related proteins (MAPRs). Furthermore, AG-205 retained its ability to increase expression of selected target genes even when expression of PGRMC1 or all MAPRs was concomitantly downregulated, indicating that neither PGRMC1 nor any MAPR is required to mediate AG-205 effect. In conclusion, although AG-205 has attractive effects encouraging its use to develop therapeutic strategies, for instance against breast cancer, our study delivers two important warning messages. First, AG-205 is not specific for PGRMC1 or other MAPRs and its mechanisms of action remain unclear. Second, due to its effects on genes involved in steroidogenesis, its use may increase the risk for endometrial pathologies resulting from imbalanced hormones concentrations.
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Affiliation(s)
- Charlotte Thieffry
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
| | - Marie Van Wynendaele
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
| | - Asena Aynaci
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
| | - Mauriane Maja
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
| | - Caroline Dupuis
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
| | - Axelle Loriot
- GEPI Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium;
| | - Etienne Marbaix
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
- Pathology Department, Cliniques Universitaires Saint-Luc, B-1200 Brussels, Belgium
| | - Patrick Henriet
- CELL Unit, de Duve Institute and Université Catholique de Louvain, B-1200 Brussels, Belgium; (C.T.); (M.V.W.); (A.A.); (M.M.); (C.D.); (E.M.)
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Jones JL, Corbett MA, Yeaman E, Zhao D, Gecz J, Gasperini RJ, Charlesworth JC, Mackey DA, Elder JE, Craig JE, Burdon KP. A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract. Eur J Hum Genet 2021; 29:1206-1215. [PMID: 33867527 PMCID: PMC8385038 DOI: 10.1038/s41431-021-00889-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/10/2021] [Accepted: 04/02/2021] [Indexed: 02/02/2023] Open
Abstract
Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye's crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24-25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24-25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 (PGRMC1) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein-protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1, which we report as a novel cataract gene.
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Affiliation(s)
- Johanna L. Jones
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS Australia
| | - Mark A. Corbett
- grid.1010.00000 0004 1936 7304Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA Australia
| | - Elise Yeaman
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS Australia
| | - Duran Zhao
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS Australia
| | - Jozef Gecz
- grid.1010.00000 0004 1936 7304Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA Australia
| | - Robert J. Gasperini
- grid.1009.80000 0004 1936 826XSchool of Medicine, University of Tasmania, Hobart, TAS Australia
| | - Jac C. Charlesworth
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS Australia
| | - David A. Mackey
- grid.1489.40000 0000 8737 8161Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, WA Australia
| | - James E. Elder
- grid.1008.90000 0001 2179 088XDepartment of Paediatrics, University of Melbourne, Melbourne, VIC Australia
| | - Jamie E. Craig
- grid.1014.40000 0004 0367 2697Department of Ophthalmology, Flinders University, Bedford Park, SA Australia
| | - Kathryn P. Burdon
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS Australia ,grid.1014.40000 0004 0367 2697Department of Ophthalmology, Flinders University, Bedford Park, SA Australia
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42
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Ershov P, Kaluzhskiy L, Mezentsev Y, Yablokov E, Gnedenko O, Ivanov A. Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context. Biomedicines 2021; 9:biomedicines9080895. [PMID: 34440098 PMCID: PMC8389681 DOI: 10.3390/biomedicines9080895] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
A global protein interactome ensures the maintenance of regulatory, signaling and structural processes in cells, but at the same time, aberrations in the repertoire of protein-protein interactions usually cause a disease onset. Many metabolic enzymes catalyze multistage transformation of cholesterol precursors in the cholesterol biosynthesis pathway. Cancer-associated deregulation of these enzymes through various molecular mechanisms results in pathological cholesterol accumulation (its precursors) which can be disease risk factors. This work is aimed at systematization and bioinformatic analysis of the available interactomics data on seventeen enzymes in the cholesterol pathway, encoded by HMGCR, MVK, PMVK, MVD, FDPS, FDFT1, SQLE, LSS, DHCR24, CYP51A1, TM7SF2, MSMO1, NSDHL, HSD17B7, EBP, SC5D, DHCR7 genes. The spectrum of 165 unique and 21 common protein partners that physically interact with target enzymes was selected from several interatomic resources. Among them there were 47 modifying proteins from different protein kinases/phosphatases and ubiquitin-protein ligases/deubiquitinases families. A literature search, enrichment and gene co-expression analysis showed that about a quarter of the identified protein partners was associated with cancer hallmarks and over-represented in cancer pathways. Our results allow to update the current fundamental view on protein-protein interactions and regulatory aspects of the cholesterol synthesis enzymes and annotate of their sub-interactomes in term of possible involvement in cancers that will contribute to prioritization of protein targets for future drug development.
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Kabe Y, Koike I, Yamamoto T, Hirai M, Kanai A, Furuhata R, Tsugawa H, Harada E, Sugase K, Hanadate K, Yoshikawa N, Hayashi H, Noda M, Uchiyama S, Yamazaki H, Tanaka H, Kobayashi T, Handa H, Suematsu M. Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1. Cancers (Basel) 2021; 13:3265. [PMID: 34209885 PMCID: PMC8269059 DOI: 10.3390/cancers13133265] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/19/2021] [Accepted: 06/25/2021] [Indexed: 12/28/2022] Open
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.
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Affiliation(s)
- Yasuaki Kabe
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ikko Koike
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tatsuya Yamamoto
- Bioorganic Research Institute, Suntory Foundation for Life Sciences (SUNBOR), 8-1-1 Seikadai, Seika, Soraku, Kyoto 619-0284, Japan
| | - Miwa Hirai
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ayaka Kanai
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ryogo Furuhata
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Erisa Harada
- Bioorganic Research Institute, Suntory Foundation for Life Sciences (SUNBOR), 8-1-1 Seikadai, Seika, Soraku, Kyoto 619-0284, Japan
| | - Kenji Sugase
- Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan
| | - Kazue Hanadate
- Cokey, Co., Ltd., 2 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Nobuji Yoshikawa
- Cokey, Co., Ltd., 2 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Hiroaki Hayashi
- Laboratory of Natural Products Chemistry, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan
| | | | - Susumu Uchiyama
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Hiroki Yamazaki
- Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo 108-8639, Japan
| | - Hirotoshi Tanaka
- Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo 108-8639, Japan
| | - Takuya Kobayashi
- Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Hiroshi Handa
- Department of Chemical Biology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
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Wang-Eckhardt L, Eckhardt M. A progesterone receptor membrane component 1 antagonist induces large vesicles independent of progesterone receptor membrane component 1 expression. Biol Chem 2021; 401:1093-1099. [PMID: 32924377 DOI: 10.1515/hsz-2019-0417] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/09/2020] [Indexed: 12/13/2022]
Abstract
Treatment of different cell lines with progesterone receptor membrane component 1 (PGRMC1) antagonist AG-205 rapidly induces the formation of large vesicular structures that likely represent endosomes. Crispr/Cas9 was used to target the PGRMC1 and progesterone receptor membrane component 2 (PGRMC2) genes in CHO-K1 and HeLa. Unexpectedly, deficiency in one of these or both genes did not inhibit the formation of enlarged vesicles by AG-205, demonstrating additional molecular target(s) of this compound besides PGRMC1. Thus, AG-205 cannot be regarded as a PGRMC1-specific antagonist. However, provided that its currently unknown target(s) will be identified, AG-205 may serve as a new reagent to study endosomal trafficking.
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Affiliation(s)
- Lihua Wang-Eckhardt
- Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Nussallee 11, D-53115 Bonn, Germany
| | - Matthias Eckhardt
- Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Nussallee 11, D-53115 Bonn, Germany
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45
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Pedroza DA, Subramani R, Tiula K, Do A, Rashiraj N, Galvez A, Chatterjee A, Bencomo A, Rivera S, Lakshmanaswamy R. Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation. J Transl Med 2021; 101:733-744. [PMID: 33903732 DOI: 10.1038/s41374-021-00594-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/21/2022] Open
Abstract
Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor α (ERα), respectively. However, the basis of communication between PR/ERα and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ERα, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ERα and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ERα by tamoxifen and ERα silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ERα expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ERα in Luminal A and B breast cancers. Targeting of PR, ERα, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors.
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Affiliation(s)
- Diego A Pedroza
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Ramadevi Subramani
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Kira Tiula
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Anthony Do
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Navya Rashiraj
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Adriana Galvez
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Animesh Chatterjee
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Alejandra Bencomo
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Servando Rivera
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Rajkumar Lakshmanaswamy
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
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46
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Estradiol-17β Regulates Expression of Luteal DNA Methyltransferases and Genes Involved in the Porcine Corpus Luteum Function In Vivo. Int J Mol Sci 2021; 22:ijms22073655. [PMID: 33915762 PMCID: PMC8037867 DOI: 10.3390/ijms22073655] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
The corpus luteum (CL) is a temporary endocrine gland vital for pregnancy establishment and maintenance. Estradiol-17β (E2) is the major embryonic signal in pigs supporting the CL's function. The mechanisms of the luteoprotective action of E2 are still unclear. The present study aimed to determine the effect of E2 on luteal expression of factors involved in CL function. An in vivo model of intrauterine E2 infusions was applied. Gilts on day 12 of pregnancy and the estrous cycle were used as referential groups. Concentrations of E2 and progesterone were elevated in CLs of gilts receiving E2 infusions, compared to placebo-treated gilts. Estradiol-17β stimulated luteal expression of DNA-methyltransferase 1 (DNMT1), but decreased expression of DNMT3B gene and protein, as well as DNMT3A protein. Similar results for DNMT3A and 3B were observed in CLs on day 12 of pregnancy compared to day 12 of the estrous cycle. Intrauterine infusions of E2 altered luteal expression of the genes involved in CL function: PTGFR, PTGES, STAR, HSD17B1, CYP19A1, and PGRMC1. Our findings indicate a role for E2 in expression regulation of factors related to CL function and a novel potential for E2 to regulate DNA methylation as putative physiological mechanisms controlling luteal gene expression.
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Mancino DN, Leicaj ML, Lima A, Roig P, Guennoun R, Schumacher M, De Nicola AF, Garay LI. Developmental expression of genes involved in progesterone synthesis, metabolism and action during the post-natal cerebellar myelination. J Steroid Biochem Mol Biol 2021; 207:105820. [PMID: 33465418 DOI: 10.1016/j.jsbmb.2021.105820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/10/2020] [Accepted: 01/12/2021] [Indexed: 10/22/2022]
Abstract
Progesterone is involved in dendritogenesis, synaptogenesis and maturation of cerebellar Purkinge cells, major sites of steroid synthesis in the brain. To study a possible time-relationship between myelination, neurosteroidogenesis and steroid receptors during development of the postnatal mouse cerebellum, we determined at postnatal days 5 (P5),18 (P18) and 35 (P35) the expression of myelin basic protein (MBP), components of the steroidogenic pathway, levels of endogenous steroids and progesterone's classical and non-classical receptors. In parallel with myelin increased expression during development, P18 and P35 mice showed higher levels of cerebellar progesterone and its reduced derivatives, higher expression of steroidogenic acute regulatory protein (StAR) mRNA, cholesterol side chain cleavage enzyme (P450scc) and 5α-reductase mRNA vs. P5 mice. Other steroids such as corticosterone and its reduced derivatives and 3β-androstanodiol (ADIOL) showed a peak increase at P18 compared to P5. Progesterone membrane receptors and binding proteins (PGRMC1, mPRα, mPRβ, mPRγ, and Sigma1 receptors) mRNAs levels increased during development while that of classical progesterone receptors (PR) remained invariable. PRKO mice showed similar MBP levels than wild type. Thus, these data suggests that progesterone and its neuroactive metabolites may play a role in postnatal cerebellar myelination.
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Affiliation(s)
- Dalila Nj Mancino
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - María Luz Leicaj
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Analia Lima
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Paulina Roig
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina
| | - Rachida Guennoun
- U1195 Inserm and University Paris Saclay, University Paris Sud, 94276 Le kremlin Bicêtre, France
| | - Michael Schumacher
- U1195 Inserm and University Paris Saclay, University Paris Sud, 94276 Le kremlin Bicêtre, France
| | - Alejandro F De Nicola
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Department of Human Biochemistry, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina
| | - Laura I Garay
- Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Department of Human Biochemistry, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina.
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48
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Cahill MA, Neubauer H. PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology. Cancers (Basel) 2021; 13:512. [PMID: 33572771 PMCID: PMC7866220 DOI: 10.3390/cancers13030512] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
This is a preface by the guest editors of the special issue of Cancers featuring the biology of progesterone (P4) receptor membrane component (PGRMC) proteins as it relates to metabolism and cancer [...].
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Affiliation(s)
- Michael A. Cahill
- School of Biomedical Sciences, Charles Sturt University, WaggaWagga, NSW 2678, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Canberra, ACT 2601, Australia
| | - Hans Neubauer
- Department of Gynecology and Obstetrics, University Women’s Hospital of Dusseldorf, 40225 Duesseldorf, Germany
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49
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Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson's patient brain-derived α-synuclein. J Neurosci Res 2021; 99:1161-1176. [PMID: 33480104 PMCID: PMC7986605 DOI: 10.1002/jnr.24782] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/03/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022]
Abstract
α‐Synuclein oligomers are thought to have a pivotal role in sporadic and familial Parkinson's disease (PD) and related α‐synucleinopathies, causing dysregulation of protein trafficking, autophagy/lysosomal function, and protein clearance, as well as synaptic function impairment underlying motor and cognitive symptoms of PD. Moreover, trans‐synaptic spread of α‐synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block α‐synuclein oligomer‐induced pathogenesis are urgently needed. Here, we show for the first time that α‐synuclein species isolated from human PD patient brain and recombinant α‐synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while α‐synuclein species isolated from non‐PD human control brain samples did not. Recombinant α‐synuclein oligomers also increased neuronal expression of lysosomal‐associated membrane protein‐2A (LAMP‐2A), the lysosomal receptor that has a critical role in chaperone‐mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma‐2 receptor antagonists as the most effective at blocking α‐synuclein oligomer‐induced trafficking deficits and LAMP‐2A upregulation in a dose‐dependent manner. These results indicate that antagonists of the sigma‐2 receptor complex may alleviate α‐synuclein oligomer‐induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related α‐synucleinopathies.
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Affiliation(s)
| | | | | | | | | | - Gary Look
- Cognition Therapeutics Inc., Pittsburgh, PA, USA
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50
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Chambers IG, Willoughby MM, Hamza I, Reddi AR. One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2021; 1868:118881. [PMID: 33022276 PMCID: PMC7756907 DOI: 10.1016/j.bbamcr.2020.118881] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023]
Abstract
Heme, as a hydrophobic iron-containing organic ring, is lipid soluble and can interact with biological membranes. The very same properties of heme that nature exploits to support life also renders heme potentially cytotoxic. In order to utilize heme, while also mitigating its toxicity, cells are challenged to tightly control the concentration and bioavailability of heme. On the bright side, it is reasonable to envision that, analogous to other transition metals, a combination of membrane-bound transporters, soluble carriers, and chaperones coordinate heme trafficking to subcellular compartments. However, given the dual properties exhibited by heme as a transition metal and lipid, it is compelling to consider the dark side: the potential role of non-proteinaceous biomolecules including lipids and nucleic acids that bind, sequester, and control heme trafficking and bioavailability. The emergence of inter-organellar membrane contact sites, as well as intracellular vesicles derived from various organelles, have raised the prospect that heme can be trafficked through hydrophobic channels. In this review, we aim to focus on heme delivery without deliverers - an alternate paradigm for the regulation of heme homeostasis through chaperone-less pathways for heme trafficking.
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Affiliation(s)
- Ian G Chambers
- Department of Animal and Avian Sciences, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20740, United States of America
| | - Mathilda M Willoughby
- School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, United States of America
| | - Iqbal Hamza
- Department of Animal and Avian Sciences, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20740, United States of America.
| | - Amit R Reddi
- School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, United States of America.
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