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Liang P, Chen JJ, Yang X, Long R, Li Y, Wang ZL, Yang PL, Liang YD. Association and functional study of ATP6V1D and GPHN gene polymorphisms with depression in Chinese population. World J Psychiatry 2025; 15:102182. [DOI: 10.5498/wjp.v15.i4.102182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/20/2025] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Depression is a disease with a significant global social burden. Single nucleotide polymorphisms (SNPs) are correlated with the development of depression. This study investigates the relationship between polymorphisms in the GPHN and ATP6V1D gene promoter regions and susceptibility to depression in the Chinese population.
AIM To provide new insights into identifying SNPs for predicting depression in the Chinese population.
METHODS We conducted a case-control study involving 555 individuals with depression and 509 healthy controls. GPHN rs8020095 and ATP6V1D rs3759755, rs10144417, rs2031564, and rs8016024 in the promoter region were genotyped using next-generation sequencing. Dual luciferase reporter genes were employed to assess the transcriptional activity of promoter regions for each SNP genotype, with transcription factors binding to each site predicted using the JASPAR database.
RESULTS Compared to healthy controls, the ATP6V1D promoter rs10144417 AG genotype (P = 0.015), rs3759755 AC/CC genotype (P = 0.036), and GPHN gene rs8020095 GA and AA genotypes (GA: P = 0.028, GG: P = 0.025) were significantly associated with a lower prevalence of depression. Linked disequilibria were present in five SNPs, with the AGATA haplotype frequency in patients significantly lower than in healthy subjects (P = 0.023). Luciferase activity of the rs3759755-A recombinant plasmid was significantly higher than that of the rs3759755-C recombinant plasmid (P = 0.026), and the rs8020095-A recombinant plasmid activity was significantly higher than that of the rs8020095-G recombinant plasmid (P = 0.001). Transcription factors orthodenticle homeobox 2, orthodenticle homeobox 1, forkhead box L1, NK homeobox 3-1, and nuclear factor, interleukin 3 regulated demonstrated binding affinity with rs3759755A > C and rs8020095A > G.
CONCLUSION This study demonstrates that SNPs (rs3759755 and rs10144417) in the promoter region of the ATP6V1D and SNP (rs8020095) of GPHN are indeed associated with susceptibility to depression.
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Affiliation(s)
- Peng Liang
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jing-Jie Chen
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Xue Yang
- Department of Geriatric Psychiatry, The First Psychiatric Hospital of Harbin, Harbin 150001, Heilongjiang Province, China
| | - Rui Long
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Yue Li
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Ling Wang
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Ping-Liang Yang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Yun-Dan Liang
- Department of Basic Medicine, Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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Zhang X, Zhang Z. Insulin receptor tyrosine kinase substrate in health and disease (Review). Mol Med Rep 2025; 31:72. [PMID: 39930824 PMCID: PMC11795247 DOI: 10.3892/mmr.2025.13437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/19/2024] [Indexed: 02/14/2025] Open
Abstract
Insulin receptor (IR) tyrosine kinase substrate (IRTKS) was first identified >20 years ago as a tyrosine‑phosphorylated IR substrate and subsequently characterized as a protein containing an inverse‑Bin‑amphiphysin‑Rvs domain. Subsequent research has shown that IRTKS functions as a scaffold protein with multiple domains, which results in diverse functions in a variety of cell activities. For example, IRTKS plays roles in regulating the formation of membrane protrusions; triggering pathogen‑driven actin assembly; modulating insulin signaling, antiviral immunity and embryonic development; and promoting tumor occurrence and progression. It is also a candidate forensic biomarker of hypothermia. Nevertheless, a systematic summary of the biological functions of IRTKS and its underlying molecular mechanism is lacking. Therefore, the present review provides a comprehensive summary of the latest advancements in IRTKS research, thereby establishing a framework for understanding the contribution of IRTKS to diverse cell processes.
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Affiliation(s)
- Xueyan Zhang
- Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Zhewen Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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3
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Xie J, Lu ZN, Bai SH, Cui XF, Lian HY, Xie CY, Wang N, Wang L, Han ZG. Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence. EMBO J 2024; 43:4542-4577. [PMID: 39192031 PMCID: PMC11480336 DOI: 10.1038/s44318-024-00212-3] [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: 04/04/2024] [Revised: 06/30/2024] [Accepted: 07/16/2024] [Indexed: 08/29/2024] Open
Abstract
Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.
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Affiliation(s)
- Jia Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhao-Ning Lu
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shi-Hao Bai
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xiao-Fang Cui
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - He-Yuan Lian
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chen-Yi Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Na Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lan Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ze-Guang Han
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
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Chen S, Xu Z, Yin J, Gu H, Shi Y, Guo C, Meng X, Li H, Huang X, Jiang Y, Wang Y. Predicting functional outcome in ischemic stroke patients using genetic, environmental, and clinical factors: a machine learning analysis of population-based prospective cohort study. Brief Bioinform 2024; 25:bbae487. [PMID: 39397424 PMCID: PMC11471838 DOI: 10.1093/bib/bbae487] [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: 04/19/2024] [Revised: 08/26/2024] [Accepted: 09/18/2024] [Indexed: 10/15/2024] Open
Abstract
Ischemic stroke (IS) is a leading cause of adult disability that can severely compromise the quality of life for patients. Accurately predicting the IS functional outcome is crucial for precise risk stratification and effective therapeutic interventions. We developed a predictive model integrating genetic, environmental, and clinical factors using data from 7819 IS patients in the Third China National Stroke Registry. Employing an 80:20 split, we randomly divided the dataset into development and internal validation cohorts. The discrimination and calibration performance of models were evaluated using the area under the receiver operating characteristic curves (AUC) for discrimination and Brier score with calibration curve in the internal validation cohort. We conducted genome-wide association studies (GWAS) in the development cohort, identifying rs11109607 (ANKS1B) as the most significant variant associated with IS functional outcome. We employed principal component analysis to reduce dimensionality on the top 100 significant variants identified by the GWAS, incorporating them as genetic factors in the predictive model. We employed a machine learning algorithm capable of identifying nonlinear relationships to establish predictive models for IS patient functional outcome. The optimal model was the XGBoost model, which outperformed the logistic regression model (AUC 0.818 versus 0.756, P < .05) and significantly improved reclassification efficiency. Our study innovatively incorporated genetic, environmental, and clinical factors for predicting the IS functional outcome in East Asian populations, thereby offering novel insights into IS functional outcome.
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Affiliation(s)
- Siding Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- Changping Laboratory, Yard 28, Science Park Road, Changping District, Beijing 102206, China
| | - Zhe Xu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Jinfeng Yin
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Hongqiu Gu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Yanfeng Shi
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Cang Guo
- Changping Laboratory, Yard 28, Science Park Road, Changping District, Beijing 102206, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Hao Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Xinying Huang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
| | - Yong Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- Changping Laboratory, Yard 28, Science Park Road, Changping District, Beijing 102206, China
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine (Beihang University and Capital Medical University), No. 37 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- Changping Laboratory, Yard 28, Science Park Road, Changping District, Beijing 102206, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, 2019RU018, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, No. 320 Yueyang Road, Shanghai 200031, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, China
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Zhang Y, Yi F, Zhang X, Song J, Cai J, Lai J, Song F. IRTKS contributes to the malignant progression of cervical cancer cells. Med Oncol 2024; 41:174. [PMID: 38869721 DOI: 10.1007/s12032-024-02410-9] [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: 03/17/2024] [Accepted: 05/23/2024] [Indexed: 06/14/2024]
Abstract
Cervical cancer (CC), one of the most aggressive tumors in women, has high risk rates of recurrence and metastasis. It is essential to study the key genes and proteins involved in CC development. IRTKS, a member of the IRSp53 family, has been reported as a tumor promoter in gastric and breast cancers. However, the biological role of IRTKS in CC is still unclear. The purpose of this study was to explore the biological function of IRTKS in CC cells in vitro and the effect of IRTKS on tumorigenesis in vivo. Siha and Hela cells were treated with si-RNA and plasmids. Cell proliferation and growth were detected by CCK8, colony formation assay and nude mouse tumorigenicity assay, respectively. Transwell assay was used to analyze cell migration and invasion. The expression of epithelial-mesenchymal transition (EMT)-related proteins was determined by western blot. IRTKS was highly expressed in CC. IRTKS contributed to the proliferation of CC cells in vitro and in vivo. Furthermore, IRTKS facilitated the migration and invasion of CC cells and modulated EMT. IRTKS plays a crucial role in CC tumorigenesis, suggesting it may be a potential key gene for new therapeutic strategies in CC.
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Affiliation(s)
- Yan Zhang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China
| | - Faping Yi
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China
| | - Xiaoxuan Zhang
- Department of Cancer Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400000, China
| | - Jing Song
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China
| | - Jing Cai
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China
| | - Jiayi Lai
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China
| | - Fangzhou Song
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, China.
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China.
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Shen S, Liao Q, Lyu P, Wang J, Lin L. Myricanol prevents aging-related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5. MedComm (Beijing) 2024; 5:e566. [PMID: 38868327 PMCID: PMC11167181 DOI: 10.1002/mco2.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 02/06/2024] [Accepted: 02/26/2024] [Indexed: 06/14/2024] Open
Abstract
Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall-related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage-induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage-induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging.
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Affiliation(s)
- Shengnan Shen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs, Artemisinin Research Center, and Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijingChina
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacauChina
| | - Qiwen Liao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacauChina
- Kobilka Institute of Innovative Drug Discovery, School of MedicineThe Chinese University of Hong KongShenzhenGuangdongChina
| | - Peng Lyu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacauChina
| | - Jigang Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs, Artemisinin Research Center, and Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijingChina
- Shenzhen Institute of Respiratory DiseaseShenzhen People's Hospital (First Affiliated Hospital of South University of Science and Technology of China and Second Affiliated Hospital of Jinan University, China)BeijingChina
- Department of OncologyThe Affiliated Hospital of Southwest Medical UniversityLuzhouChina
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacauChina
- Department of Pharmaceutical Sciences and Technology, Faculty of Health SciencesUniversity of MacauMacauChina
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Yagi Y, Abe R, Tani H. Exploring IDI2-AS1, OIP5-AS1, and LITATS1: Changes in Long Non-coding RNAs Induced by the Poly I:C Stimulation. Biol Pharm Bull 2024; 47:1144-1147. [PMID: 38866523 DOI: 10.1248/bpb.b24-00037] [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] [Indexed: 06/14/2024]
Abstract
Long non-coding RNAs (lncRNAs) are sequences longer than 200 nucleotides, but they do not encode proteins. Nevertheless, they have significant roles in diverse biological functions. It remains unclear how viral infections trigger the expression of lncRNAs. In our previous research, we revealed a distinct type of lncRNAs with a lifespan under 4 h in human HeLa cells. These short-lived lncRNAs might be associated with numerous regulatory roles. Given their potential impact on human physiology, these short-lived lncRNAs could be key indicators to measure polyinosinic:polycytidylic acid (poly I:C) stimulation. In our recent work, we discovered three lncRNAs: IDI2-AS1, OIP5-AS1, and LITATS1. After exposure to poly I:C, imitating viral assault in human A549 cells, IDI2-AS1 levels dropped significantly while OIP5-AS1 and LITATS1 levels rose markedly. Our results indicate that short-lived lncRNAs respond to poly I:C stimulation, exhibiting substantial changes in expression. This indicates that the understanding the role of lncRNAs in the host response to viral infection and the potential for these molecules to serve as novel therapeutic targets.
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Affiliation(s)
- Yuka Yagi
- Department of Clinical Pharmacy, Yokohama University of Pharmacy
- Department of Health Pharmacy, Yokohama University of Pharmacy
| | - Rina Abe
- Department of Clinical Pharmacy, Yokohama University of Pharmacy
- Department of Health Pharmacy, Yokohama University of Pharmacy
| | - Hidenori Tani
- Department of Health Pharmacy, Yokohama University of Pharmacy
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Cui X, Shang X, Xie J, Xie C, Tang Z, Luo Q, Wu C, Wang G, Wang N, He K, Wang L, Huang L, Wan B, Roeder RG, Han ZG. Cooperation between IRTKS and deubiquitinase OTUD4 enhances the SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via suppressing E-cadherin expression. Cancer Lett 2023; 575:216404. [PMID: 37739210 DOI: 10.1016/j.canlet.2023.216404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/31/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
Elevated expression and genetic aberration of IRTKS, also named as BAIAP2L1, have been observed in many tumors, especially in tumor progression. however, the molecular and cellular mechanisms involved in the IRTKS-enhanced tumor progression are obscure. Here we show that higher IRTKS level specifically increases histone H3 lysine 9 trimethylation (H3K9me3) by promoting accumulation of the histone methyltransferase SETDB1. Furthermore, we reveal that IRTKS recruits the deubiquitinase OTUD4 to remove Lys48-linked polyubiquitination at K182/K1050 sites of SETDB1, thus blocking SETDB1 degradation via the ubiquitin-proteasome pathway. Interestingly, the enhanced IRTKS-OTUD4-SETDB1-H3K9me3 axis leads to a general decrease in chromatin accessibility, which inhibits transcription of CDH1 encoding E-cadherin, a key molecule essential for maintaining epithelial cell phenotype, and therefore results in epithelial-mesenchymal transition (EMT) and malignant cell metastasis. Clinically, the elevated IRTKS levels in tumor specimens correlate with SETDB1 levels, but negatively associate with survival time. Our data reveal a novel mechanism for the IRTKS-enhanced tumor progression, where IRTKS cooperates with OTUD4 to enhance SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via suppressing E-cadherin expression. This study also provides a potential approach to reduce the activity and stability of the known therapeutic target SETDB1 possibly through regulating IRTKS or deubiquitinase OTUD4.
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Affiliation(s)
- Xiaofang Cui
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xueying Shang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jia Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chenyi Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhanyun Tang
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, 10065, USA
| | - Qing Luo
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chongchao Wu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Guangxing Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Na Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Kunyan He
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lan Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Liyu Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Bingbing Wan
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Robert G Roeder
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, 10065, USA
| | - Ze-Guang Han
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
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Nulali J, Zhan M, Zhang K, Tu P, Liu Y, Song H. Osteoglycin: An ECM Factor Regulating Fibrosis and Tumorigenesis. Biomolecules 2022; 12:1674. [PMID: 36421687 PMCID: PMC9687868 DOI: 10.3390/biom12111674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 08/27/2023] Open
Abstract
The extracellular matrix (ECM) is made up of noncellular components that have special properties for influencing cell behavior and tissue structure. Small leucine-rich proteoglycans (SLRPs) are nonfibrillar ECM components that serve as structural scaffolds and signaling molecules. osteoglycin (OGN), a class III SLRP, is a ubiquitous ECM component that not only helps to organize the extracellular matrix but also regulates a number of important biological processes. As a glycosylated protein in the ECM, OGN was originally considered to be involved in fiber assembly and was reported to have a connection with fibrosis. In addition to these functions, OGN is found in a variety of cancer tissues and is implicated in cellular processes linked to tumorigenesis, including cell proliferation, invasion, metastasis, and epithelial-mesenchymal transition (EMT). In this review, we summarize the structure and functions of OGN as well as its biological and clinical importance in the context of fibrotic illness and tumorigenesis. This review aims to improve our understanding of OGN and provide some new strategies for the treatment of fibrosis and cancer.
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Affiliation(s)
- Jiayida Nulali
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ming Zhan
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Kaiwen Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Pinghui Tu
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yu Liu
- Department of Respiration, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200070, China
| | - Huaidong Song
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
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10
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Ebadi Zavieh S, Safari F. The Antitumor Activity of hAMSCs Secretome in HT-29 Colon Cancer Cells Through Downregulation of EGFR/c-Src/IRTKS Expression and p38/ERK1/2 Phosphorylation. Cell Biochem Biophys 2022; 80:395-402. [PMID: 35150389 DOI: 10.1007/s12013-022-01066-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2022] [Indexed: 11/03/2022]
Abstract
Colon cancer is considered as one of the main causes of mortality worldwide. Identifying a novel and more effective platform with fewer side effects is still progress. In various cancer types, Epidermal growth factor receptor (EGFR) and c-Src (a key mediator in EGFR signaling pathway) are the key targets for cancer therapy. Moreover, insulin receptor tyrosine kinase substrate (IRTKS or BAI1-associated protein 2-like 1: BAIAP2L1) is a member of the subfamily of inverse BAR (I-BAR) domain proteins, which mediates cell morphology and movement through regulation of actin polymerization. In this study, we employed a co-culture system using Transwell six-well plates. After 72 h, hAMSCs-treated HT-29 cells, EGFR, c-Src, IRTKS, p38, and ERK1/2 expression were analyzed using quantitative real time PCR (qRT-PCR) and western blot methods. The significant reduction in tumor cell growth and motility through downregulation of EGFR/c-Src/IRTKS expression and p38/ERK1/2 phosphorylation in HT-29 cells was demonstrated based on 2D and 3D cell culture models. The induction of cellular apoptosis was also found. Our results support the idea that the hAMSCS secretome has therapeutic effects on cancer cells. However, further experiments will be required to identify the exact molecular mechanisms.
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Affiliation(s)
- Shamin Ebadi Zavieh
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
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11
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Mizusawa N, Harada N, Iwata T, Ohigashi I, Itakura M, Yoshimoto K. Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells. Islets 2022; 14:1-13. [PMID: 34636707 PMCID: PMC8812782 DOI: 10.1080/19382014.2021.1982325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to identify genes that are specifically expressed in pancreatic islet β-cells (hereafter referred to as β-cells). Large-scale complementary DNA-sequencing analysis was performed for 3,429 expressed sequence tags derived from murine MIN6 β-cells, through homology comparisons using the GenBank database. Three individual ESTs were found to code for protease serine S1 family member 53 (Prss53). Prss53 mRNA is processed into both a short and long form, which encode 482 and 552 amino acids, respectively. Transient overexpression of myc-tagged Prss53 in COS-7 cells showed that Prss53 was strongly associated with the luminal surfaces of organellar membranes and that it underwent signal peptide cleavage and N-glycosylation. Immunoelectron microscopy and western blotting revealed that Prss53 localized to mitochondria in MIN6 cells. Short hairpin RNA-mediated Prss53 knockdown resulted in Ppargc1a downregulation and Ucp2 and Glut2 upregulation. JC-1 staining revealed that the mitochondria were depolarized in Prss53-knockdown MIN6 cells; however, no change was observed in glucose-stimulated insulin secretion. Our results suggest that mitochondrial Prss53 expression plays an important role in maintaining the health of β-cells.
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Affiliation(s)
- Noriko Mizusawa
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
- CONTACT Noriko Mizusawa Department of Oral Bioscience, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-Kuramoto-cho, Tokushima City770-8504, Japan
| | - Nagakatsu Harada
- Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, Shimane, Japan
| | - Takeo Iwata
- Department of Functional Morphology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | - Izumi Ohigashi
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Mitsuo Itakura
- Division of Genetic Information, Institute for Genome Research, Tokushima University, Tokushima, Japan
| | - Katsuhiko Yoshimoto
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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12
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Su Q, Yang Z, Guo X, Mo W, Li X. Tubulin polymerization promoting protein family member 3 (TPPP3) overexpression inhibits cell proliferation and invasion in nasopharyngeal carcinoma. Bioengineered 2021; 12:8485-8495. [PMID: 34668461 PMCID: PMC8806723 DOI: 10.1080/21655979.2021.1984006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The function of tubulin polymerization promoting protein family member 3 (TPPP3) in tumor cells is complicated, and the role of TPPP3 in nasopharyngeal carcinoma (NPC) remains unclear. This study aims to explore the expression of TPPP3 in NPC and its effect on NPC cells. The expression of TPPP3 in NPC tissues and other cancers were analyzed by using the Oncomine and Gene Expression Omnibus (GEO) databases. The mRNA and protein of TPPP3 were detected in NPC tissues by quantitative real-time PCR and immunohistochemistry. Furthermore, TPPP3 was overexpressed in 5-8 F and HONE1 cell lines by lentivirus transfection, and functional analysis of TPPP3 in NPC was evaluated through in vitro experiments. The expression of TPPP3 was significantly down-regulated in NPC tissues and cells. Overexpression of TPPP3 significantly inhibited proliferation of 5-8 F and HONE1 cells in vitro. In addition, overexpression of TPPP3 significantly attenuated the invasion ability of 5-8 F, HONE1 cells in vitro, but have no significant effect on migration ability. Furthermore, TPPP3 overexpression diminished the expression of MMP-2 and MMP-9 mRNA. By analyzing dataset GSE12452, it was interesting that TPPP3 high expression group mainly functioned in B cell receptor signaling pathway, cell cycle and DNA replication. In conclusion, our results suggest that TPPP3 may be considered as an antioncogene, which plays an important role in the occurrence and progression of NPC.Abbreviations: TPPP3: tubulin polymerization promoting protein family member 3; NPC: nasopharyngeal carcinoma; GEO: Gene Expression Omnibus; qRT-PCR: quantitative real-time PCR; GFP: green fluorescence protein; MOI, transfected multiplicity of infection; CCK-8: cell counting kit-8; OD: optical density; GSEA: gene set enrichment analysis; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; MMP-2: matrix metalloproteinase-2; MMP-9: matrix metalloproteinase-9.
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Affiliation(s)
- Qisheng Su
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zheng Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaobin Guo
- Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Wuning Mo
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaohong Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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13
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Chen L, Ye K, Feng X, Li L, Li Q, Huang Y, Wang X, Li R, Hu C, Yang Z, Lu B, Yang Y, Wen J, Zhang Z, He M, Wang Q, Zhou W, Li Y, Liu N, Huang J, Shen Q, Yao Q, Hu R. PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation. Nutr Metab (Lond) 2021; 18:54. [PMID: 34074311 PMCID: PMC8170790 DOI: 10.1186/s12986-021-00579-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/14/2021] [Indexed: 02/06/2023] Open
Abstract
Background The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin–proteasome inhibitor PS-341 could regulate the function of TM4. Methods The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. Results TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065–2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. Conclusions PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00579-8.
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Affiliation(s)
- Lili Chen
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Kuanping Ye
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Xiaocheng Feng
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lianxi Li
- Department of Endocrinology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Qin Li
- Department of Endocrinology, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Ying Huang
- Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xuanchun Wang
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Rumei Li
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Cheng Hu
- Department of Endocrinology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Bin Lu
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Yehong Yang
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Jie Wen
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Zhaoyun Zhang
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Min He
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Qinghua Wang
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Wenbai Zhou
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Yintao Li
- Department of Chemotherapy, Shandong Tumor Hospital, Shandong University, Jinan, China
| | - Naijia Liu
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Jinya Huang
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Qiwei Shen
- Department of General Surgery, Huashan Hospital Fudan University, Shanghai, China
| | - Qiyuan Yao
- Department of General Surgery, Huashan Hospital Fudan University, Shanghai, China
| | - Renming Hu
- Department of Endocrinology, Huashan Hospital Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China. .,Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China.
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14
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Dumontet T, Martinez A. Adrenal androgens, adrenarche, and zona reticularis: A human affair? Mol Cell Endocrinol 2021; 528:111239. [PMID: 33676986 DOI: 10.1016/j.mce.2021.111239] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/11/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
In humans, reticularis cells of the adrenal cortex fuel the production of androgen steroids, constituting the driver of numerous morphological changes during childhood. These steps are considered a precocious stage of sexual maturation and are grouped under the term "adrenarche". This review describes the molecular and enzymatic characteristics of the zona reticularis, along with the possible signals and mechanisms that control its emergence and the associated clinical features. We investigate the differences between species and discuss new studies such as genetic lineage tracing and transcriptomic analysis, highlighting the rodent inner cortex's cellular and molecular heterogeneity. The recent development and characterization of mouse models deficient for Prkar1a presenting with adrenocortical reticularis-like features prompt us to review our vision of the mouse adrenal gland maturation. We expect these new insights will help increase our understanding of the adrenarche process and the pathologies associated with its deregulation.
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Affiliation(s)
- Typhanie Dumontet
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA; Training Program in Organogenesis, Center for Cell Plasticity and Organ Design, University of Michigan, Ann Arbor, MI, USA.
| | - Antoine Martinez
- Génétique, Reproduction et Développement (GReD), Centre National de La Recherche Scientifique CNRS, Institut National de La Santé & de La Recherche Médicale (INSERM), Université Clermont-Auvergne (UCA), France.
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15
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Chen Q, Wang WJ, Jia YX, Yuan H, Wu PF, Ge WL, Meng LD, Huang XM, Shen P, Yang TY, Miao Y, Zhang JJ, Jiang KR. Effect of the transcription factor YY1 on the development of pancreatic endocrine and exocrine tumors: a narrative review. Cell Biosci 2021; 11:86. [PMID: 33985581 PMCID: PMC8120816 DOI: 10.1186/s13578-021-00602-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 05/04/2021] [Indexed: 12/19/2022] Open
Abstract
Pancreatic tumors are classified into endocrine and exocrine types, and the clinical manifestations in patients are nonspecific. Most patients, especially those with pancreatic ductal adenocarcinoma (PDAC), have lost the opportunity to receive for the best treatment at the time of diagnosis. Although chemotherapy and radiotherapy have shown good therapeutic results in other tumors, their therapeutic effects on pancreatic tumors are minimal. A multifunctional transcription factor, Yin-Yang 1 (YY1) regulates the transcription of a variety of important genes and plays a significant role in diverse tumors. Studies have shown that targeting YY1 can improve the survival time of patients with tumors. In this review, we focused on the mechanism by which YY1 affects the occurrence and development of pancreatic tumors. We found that a YY1 mutation is specific for insulinomas and has a role in driving the degree of malignancy. In addition, changes in the circadian network are a key causative factor of PDAC. YY1 promotes pancreatic clock progression and induces malignant changes, but YY1 seems to act as a tumor suppressor in PDAC and affects many biological behaviors, such as proliferation, migration, apoptosis and metastasis. Our review summarizes the progress in understanding the role of YY1 in pancreatic endocrine and exocrine tumors and provides a reasonable assessment of the potential for therapeutic targeting of YY1 in pancreatic tumors.
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Affiliation(s)
- Qun Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Wu-Jun Wang
- Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China
| | | | - Hao Yuan
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Peng-Fei Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Wan-Li Ge
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Ling-Dong Meng
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Xu-Min Huang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Peng Shen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Tao-Yue Yang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.,Nanjing Medical University, Nanjing, China
| | - Jing-Jing Zhang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China. .,Nanjing Medical University, Nanjing, China.
| | - Kui-Rong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China. .,Nanjing Medical University, Nanjing, China.
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16
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Su B, Zhang QY, Li XS, Yu HM, Li P, Ma JH, Cao HM, Sun F, Zhao SX, Zheng CX, Ru Y, Song HD. The expression of mimecan in adrenal tissue plays a role in an organism's responses to stress. Aging (Albany NY) 2021; 13:13087-13107. [PMID: 33971622 PMCID: PMC8148509 DOI: 10.18632/aging.202991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/02/2021] [Indexed: 01/07/2023]
Abstract
Mimecan encodes a secretory protein that is secreted into the human serum as two mature proteins with molecular masses of 25 and 12 kDa. We found 12-kDa mimecan to be a novel satiety hormone mediated by the upregulation of the expression of interleukin (IL)-1β and IL-6 in the hypothalamus. Mimecan was found to be expressed in human pituitary corticotroph cells and was up-regulated by glucocorticoids, while the secretion of adrenocorticotropic hormone (ACTH) in pituitary corticotroph AtT-20 cells was induced by mimecan. However, the effects of mimecan in adrenal tissue on the hypothalamic–pituitary–adrenal (HPA) axis functions remain unknown. We demonstrated that the expression of mimecan in adrenal tissues is significantly downregulated by hypoglycemia and scalded stress. It was down-regulated by ACTH, but upregulated by glucocorticoids through in vivo and in vitro studies. We further found that 12-kDa mimecan fused protein increased the corticosterone secretion of adrenal cells in vivo and in vitro. Interestingly, compared to litter-mate mice, the diurnal rhythm of corticosterone secretion was disrupted under basal conditions, and the response to restraint stress was stronger in mimecan knockout mice. These findings suggest that mimecan stimulates corticosterone secretion in the adrenal tissues under basal conditions; however, the down-regulated expression of mimecan by increased ACTH secretion after stress in adrenal tissues might play a role in maintaining the homeostasis of an organism’s responses to stress.
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Affiliation(s)
- Bin Su
- Department of Blood Transfusion and Endocrinology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Qian-Yue Zhang
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Xue-Song Li
- Department of Endocrine Metabolism, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Hui-Min Yu
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Ping Li
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Jun-Hua Ma
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Huang-Ming Cao
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Fei Sun
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Shuang-Xia Zhao
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
| | - Cui-Xia Zheng
- Department of Respiration, Yangpu Hospital, Tongji University, Shanghai 200090, China
| | - Ying Ru
- Department of Endocrinology and Metabolism, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, Anhui, China.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Huai-Dong Song
- The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China
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17
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Wang S, Liu Z, Ma YM, Guan X, Jiang Z, Sun P, Liu ER, Zhang YK, Wang HY, Wang XS. Upregulated insulin receptor tyrosine kinase substrate promotes the proliferation of colorectal cancer cells via the bFGF/AKT signaling pathway. Gastroenterol Rep (Oxf) 2020; 9:166-175. [PMID: 34026224 PMCID: PMC8128016 DOI: 10.1093/gastro/goaa032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 04/02/2020] [Accepted: 05/06/2020] [Indexed: 11/14/2022] Open
Abstract
Background Some recent studies on insulin receptor tyrosine kinase substrate (IRTKS) have focused more on its functions in diseases. However, there is a lack of research on the role of IRTKS in carcinomas and its mechanism remains ambiguous. In this study, we aimed to clarify the role and mechanism of IRTKS in the carcinogenesis of colorectal cancer (CRC). Methods We analysed the expression of IRTKS in CRC tissues and normal tissues by researching public databases. Cancer tissues and adjacent tissues of 67 CRC patients who had undergone radical resection were collected from our center. Quantitative real-time polymerase chain reaction and immunohistochemistry were performed in 52 and 15 pairs of samples, respectively. In vitro and in vivo experiments were conducted to observe the effect of IRTKS on CRC cells. Gene Set Enrichment Analysis and Metascape platforms were used for functional annotation and enrichment analysis. We detected the protein kinase B (AKT) phosphorylation and cell viability of SW480 transfected with small interfering RNAs (siRNAs) with or without basic fibroblast growth factor (bFGF) through immunoblotting and proliferation assays. Results The expression of IRTKS in CRC tissues was higher than that in adjacent tissues and normal tissues (all P < 0.05). Disease-free survival of patients with high expression was shorter. Overexpression of IRTKS significantly increased the proliferation rate of CRC cells in vitro and the number of tumor xenografts in vivo. The phosphorylation level of AKT in CRC cells transfected with pLVX-IRTKS was higher than that in the control group. Furthermore, siRNA-IRTKS significantly decreased the proliferation rate of tumor cells and the phosphorylation level of AKT induced by bFGF. Conclusion IRTKS mediated the bFGF-induced cell proliferation through the phosphorylation of AKT in CRC cells, which may contribute to tumorigenicity in vivo.
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Affiliation(s)
- Song Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China
| | - Zheng Liu
- Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Yi-Ming Ma
- State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Xu Guan
- Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Zheng Jiang
- Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Peng Sun
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China
| | - En-Rui Liu
- Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Yu-Kun Zhang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China
| | - Hong-Ying Wang
- State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Xi-Shan Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P. R. China.,Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
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Chen Q, Yang C, Chen L, Zhang JJ, Ge WL, Yuan H, Meng LD, Huang XM, Shen P, Miao Y, Jiang KR. YY1 targets tubulin polymerisation-promoting protein to inhibit migration, invasion and angiogenesis in pancreatic cancer via p38/MAPK and PI3K/AKT pathways. Br J Cancer 2019; 121:912-921. [PMID: 31631174 PMCID: PMC6888832 DOI: 10.1038/s41416-019-0604-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/21/2019] [Accepted: 09/27/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PDAC) is a highly invasive cancer with poor prognosis. Recent research has found that the transcription factor Yin Yang 1 (YY1) plays an inhibitory role in the development of pancreatic cancer. It has been reported that tubulin polymerisation-promoting protein (TPPP) plays an indispensable role in a variety of tumours, but its expression and role in pancreatic cancer have not yet been elucidated. METHODS In this study, we performed ChIP-sequencing and found that YY1 directly binds to the promoter region of TPPP. The expression of TPPP in pancreatic cancer was detected by western blotting and immunohistochemistry. Four-week-old male BALB/c-nude mice were used to assess the effect of TPPP on pancreatic cancer. RESULTS Immunohistochemistry revealed that TPPP was expressed at low levels in pancreatic cancer tissues, and was associated with blood vessel invasion. The results from vivo experiments have showed that TPPP could enhance the migration and invasion of pancreatic cancer. Further experiments showed that YY1 could inhibit the migration, invasion and angiogenesis of pancreatic cancer cells by downregulating TPPP via p38/MAPK and PI3K/AKT pathways. CONCLUSION Our study demonstrates that TPPP may act as a promoter and may serve as a novel target for the treatment of pancreatic cancer.
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Affiliation(s)
- Qun Chen
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Chuang Yang
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Lei Chen
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jing-Jing Zhang
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Wan-Li Ge
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Hao Yuan
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Ling-Dong Meng
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Xu-Min Huang
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Peng Shen
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. .,Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Kui-Rong Jiang
- Pancreas Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. .,Pancreas Institute, Nanjing Medical University, Nanjing, China.
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19
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IRTKS Promotes Insulin Signaling Transduction through Inhibiting SHIP2 Phosphatase Activity. Int J Mol Sci 2019; 20:ijms20112834. [PMID: 31212584 PMCID: PMC6600216 DOI: 10.3390/ijms20112834] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/01/2019] [Accepted: 06/06/2019] [Indexed: 12/27/2022] Open
Abstract
Insulin signaling is mediated by a highly integrated network that controls glucose metabolism, protein synthesis, cell growth, and differentiation. Our previous work indicates that the insulin receptor tyrosine kinase substrate (IRTKS), also known as BAI1-associated protein 2-like 1 (BAIAP2L1), is a novel regulator of insulin network, but the mechanism has not been fully studied. In this work we reveal that IRTKS co-localizes with Src homology (SH2) containing inositol polyphosphate 5-phosphatase-2 (SHIP2), and the SH3 domain of IRTKS directly binds to SHIP2’s catalytic domain INPP5c. IRTKS suppresses SHIP2 phosphatase to convert phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3, PIP3) to phosphatidylinositol (3,4) bisphosphate (PI(3,4)P2). IRTKS-knockout significantly increases PI(3,4)P2 level and decreases cellular PI(3,4,5)P3 content. Interestingly, the interaction between IRTKS and SHIP2 is dynamically regulated by insulin, which feeds back and affects the tyrosine phosphorylation of IRTKS. Furthermore, IRTKS overexpression elevates PIP3, activates the AKT–mTOR signaling pathway, and increases cell proliferation. Thereby, IRTKS not only associates with insulin receptors to activate PI3K but also interacts with SHIP2 to suppress its activity, leading to PIP3 accumulation and the activation of the AKT–mTOR signaling pathway to modulate cell proliferation.
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20
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Imada T, Nakamura S, Hisamura R, Izuta Y, Jin K, Ito M, Kitamura N, Tanaka KF, Mimura M, Shibuya I, Tsubota K. Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor. Sci Rep 2017; 7:6965. [PMID: 28761086 PMCID: PMC5537296 DOI: 10.1038/s41598-017-06022-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 06/07/2017] [Indexed: 11/18/2022] Open
Abstract
Tears are extracellular fluid secreted from the lacrimal gland (LG). Tears consist of a dynamic tri-layered film composed of secretions from the LG, Meibomian gland, and conjunctival goblet cells. The LG secretes the aqueous component of the tear, the Meibomian gland secretes the lipid component, and conjunctival goblet cells secrete mucin. The regulation of LG activity via the autonomic nervous system has been recognized as fundamental to maintaining aqueous tear flow. Here, we describe the role of a hormone, peripheral serotonin, in tear secretion. We found that blood serotonin concentration, changed by feeding a diet deprived of the serotonin precursor tryptophan, correlated with tear secretion, and that a sustained decrease in serotonin resulted in LG atrophy and autophagy. The combination of a decrease in serotonin with the interruption of autonomic neural stimuli to the LG preceded these alterations. Furthermore, we found that the serotonin type 3a receptor expressed in LG acinar cells is involved in tear secretion via intracellular calcium mobilization. Our findings demonstrate that hormonal regulation by serotonin, in cooperation with the autonomic nervous system, regulates tear secretion.
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Affiliation(s)
- Toshihiro Imada
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Shigeru Nakamura
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan.
| | - Ryuji Hisamura
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Yusuke Izuta
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Kai Jin
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Naoki Kitamura
- Department of Veterinary Physiology, Faculty of Agriculture, Tottori University, 4-101, Koyama-cho Minami, Tottori, 680-8553, Japan
| | - Kenji F Tanaka
- Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Masaru Mimura
- Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Izumi Shibuya
- Department of Veterinary Physiology, Faculty of Agriculture, Tottori University, 4-101, Koyama-cho Minami, Tottori, 680-8553, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo, 160-8582, Japan.
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Li Y, Xu Y, Ye K, Wu N, Li J, Liu N, He M, Lu B, Zhou W, Hu R. Knockdown of Tubulin Polymerization Promoting Protein Family Member 3 Suppresses Proliferation and Induces Apoptosis in Non-Small-Cell Lung Cancer. J Cancer 2016; 7:1189-96. [PMID: 27390593 PMCID: PMC4934026 DOI: 10.7150/jca.14790] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 04/26/2016] [Indexed: 12/22/2022] Open
Abstract
Our previous studies demonstrated that depletion of tubulin polymerization promoting protein family member 3 (TPPP3) inhibits proliferation and induces apoptosis of HeLa cells. However, the expression and roles of TPPP3 in cancers remain largely unknown. In this study, we investigated the expression of TPPP3 in clinicopathological correlations in non-small-cell lung cancer (NSCLC) samples by immunohistochemistry. TPPP3 expression was significantly upregulated in NSCLC tissues, and high TPPP3 expression was positively associated with tumor size, lymph node metastasis, clinical stage, and poor survival. Furthermore, knockdown of TPPP3 by shRNA significantly inhibited cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. In addition, depletion of TPPP3 inhibited lung cancer growth in vivo in the xenografts of H1299 cells; this effect was accompanied by the suppression of Ki67 expression. Our data suggested that TPPP3 might act as an oncogene in NSCLC. TPPP3 warrants consideration as a therapeutic candidate with anti-tumor potential.
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Affiliation(s)
- Yintao Li
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China; 2. Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, P.R. China
| | - Yali Xu
- 3. Department of Pathology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Kuanping Ye
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Nan Wu
- 4. Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Junfeng Li
- 5. Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China
| | - Naijia Liu
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Min He
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Bin Lu
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Wenbai Zhou
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Renming Hu
- 1. Department of Endocrinology and Metabolism, Institute of Endocrinology and Diabetology, Huashan Hospital, Fudan University, Shanghai, P.R. China
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22
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Yuan S, Jin J, Shi J, Hou Y. Inhibitor of growth-4 is a potential target for cancer therapy. Tumour Biol 2016; 37:4275-9. [PMID: 26803518 DOI: 10.1007/s13277-016-4842-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 01/12/2016] [Indexed: 12/11/2022] Open
Abstract
The inhibitor of growth-4 (ING-4) belongs to the inhibitor of growth (ING) family that is a type II tumor suppressor gene including five members (ING1-5). As a tumor suppressor, ING4 inhibits tumor growth, invasion, and metastasis by multiple signaling pathways. In addition to that, ING4 can facilitate cancer cell sensitivity to chemotherapy and radiotherapy. Although ING4 loss is observed for many types of cancers, increasing evidences show that ING4 can be used for gene therapy. In this review, the recent progress of ING4 regulating tumorigenesis is discussed.
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Affiliation(s)
- Shuping Yuan
- Department of Oncology, Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, 212017, People's Republic of China.,Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Jianhua Jin
- Department of Oncology, Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, 212017, People's Republic of China
| | - Juanjuan Shi
- Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
| | - Yongzhong Hou
- Department of Oncology, Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, 212017, People's Republic of China. .,Institute of Life Sciences, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
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23
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Mimecan, a Hormone Abundantly Expressed in Adipose Tissue, Reduced Food Intake Independently of Leptin Signaling. EBioMedicine 2015; 2:1718-24. [PMID: 26870797 PMCID: PMC4740298 DOI: 10.1016/j.ebiom.2015.09.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 09/16/2015] [Accepted: 09/25/2015] [Indexed: 01/29/2023] Open
Abstract
Adipokines such as leptin play important roles in the regulation of energy metabolism, particularly in the control of appetite. Here, we describe a hormone, mimecan, which is abundantly expressed in adipose tissue. Mimecan was observed to inhibit food intake and reduce body weight in mice. Intraperitoneal injection of a mimecan-maltose binding protein (-MBP) complex inhibited food intake in C57BL/6J mice, which was attenuated by pretreatment with polyclonal antibody against mimecan. Notably, mimecan-MBP also induced anorexia in Ay/a and db/db mice. Furthermore, the expression of interleukin (IL)-1β and IL-6 was up-regulated in the hypothalamus by mimecan-MBP, as well as in N9 microglia cells by recombinant mouse mimecan. Taken together, the results suggest that mimecan is a satiety hormone in adipose tissue, and that mimecan inhibits food intake independently of leptin signaling by inducing IL-1β and IL-6 expression in the hypothalamus.
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24
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Xia P, Wang S, Xiong Z, Ye B, Huang LY, Han ZG, Fan Z. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat Commun 2015; 6:8132. [PMID: 26348439 PMCID: PMC4569712 DOI: 10.1038/ncomms9132] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 07/22/2015] [Indexed: 12/16/2022] Open
Abstract
RNA virus infection is recognized by the RIG-I family of receptors that activate the mitochondrial adaptor MAVS, leading to the clearance of viruses. Antiviral signalling activation requires strict modulation to avoid damage to the host from exacerbated inflammation. Insulin receptor tyrosine kinase substrate (IRTKS) participates in actin bundling and insulin signalling and its deficiency causes insulin resistance. However, whether IRTKS is involved in the regulation of innate immunity remains elusive. Here we show that IRTKS deficiency causes enhanced innate immune responses against RNA viruses. IRTKS-mediated suppression of antiviral responses depends on the RIG-I-MAVS signalling pathway. IRTKS recruits the E2 ligase Ubc9 to sumoylate PCBP2 in the nucleus, which causes its cytoplasmic translocation during viral infection. The sumoylated PCBP2 associates with MAVS to initiate its degradation, leading to downregulation of antiviral responses. Thus, IRTKS functions as a negative modulator of excessive inflammation.
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Affiliation(s)
- Pengyan Xia
- Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
| | - Shuo Wang
- Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
| | - Zhen Xiong
- Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.,University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Buqing Ye
- Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
| | - Li-Yu Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.,Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China
| | - Ze-Guang Han
- Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.,Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China
| | - Zusen Fan
- Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.,University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
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25
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Chao A, Tsai CL, Jung SM, Chuang WC, Kao C, Hsu A, Chen SH, Lin CY, Lee YC, Lee YS, Wang TH, Wang HS, Lai CH. BAI1-Associated Protein 2-Like 1 (BAIAP2L1) Is a Potential Biomarker in Ovarian Cancer. PLoS One 2015. [PMID: 26222696 PMCID: PMC4519316 DOI: 10.1371/journal.pone.0133081] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Brain-specific angiogenesis inhibitor 1 (BAI1)-associated protein 2-like 1 (BAIAP2L1), also known as insulin receptor tyrosine kinase substrate (IRTKS), is involved in plasma membrane protrusion and actin formation during cell morphogenesis and migration. BAIAP2L1 is recently reported to promote cell proliferation through activation of the EGFR-ERK pathway in hepatocellular carcinoma. In this study, we report the first comprehensive study of BAIAP2L1 upregulation in human ovarian cancer. Upregulation of BAIAP2L1 in ovarian tumors was first found during RNA screening and confirmed by immunohistochemical studies on ovarian cancers and other cancer types. Significant upregulation of BAIAP2L1 in ovarian cancer was validated by analyzing multiple independent cohorts in publicly available data sets. Furthermore, BAIAP2L1 protein expression in metastatic lesions was higher than the corresponding primary tumors. Functional assays in ovarian cancer cells revealed that BAIAP2L1 is involved in promoting cell proliferation and avoiding apoptosis. In conclusion, results of this study not only indicate that BAIAP2L1 can be used as a biomarker for human ovarian cancer but also reveal its role in cancer biology. Further elucidation of the role of BAIAP2L1 in context of the insulin receptor signaling pathways of cancer cells is warranted for developing cancer therapeutics by targeting cancer-specific metabolism.
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Affiliation(s)
- Angel Chao
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Chia-Lung Tsai
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shih-Ming Jung
- Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Wei-Chi Chuang
- Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chieh Kao
- Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - An Hsu
- Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shun-Hua Chen
- Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chiao-Yun Lin
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Yi-Chao Lee
- College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yun-Shien Lee
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Biotechnology, Ming-Chuan University, Taoyuan, Taiwan
- * E-mail: (THW); (YSL)
| | - Tzu-Hao Wang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- * E-mail: (THW); (YSL)
| | - Hsin-Shih Wang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Chyong-Huey Lai
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
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26
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Abstract
The purpose of this article is to review fundamentals in adrenal gland histophysiology. Key findings regarding the important signaling pathways involved in the regulation of steroidogenesis and adrenal growth are summarized. We illustrate how adrenal gland morphology and function are deeply interconnected in which novel signaling pathways (Wnt, Sonic hedgehog, Notch, β-catenin) or ionic channels are required for their integrity. Emphasis is given to exploring the mechanisms and challenges underlying the regulation of proliferation, growth, and functionality. Also addressed is the fact that while it is now well-accepted that steroidogenesis results from an enzymatic shuttle between mitochondria and endoplasmic reticulum, key questions still remain on the various aspects related to cellular uptake and delivery of free cholesterol. The significant progress achieved over the past decade regarding the precise molecular mechanisms by which the two main regulators of adrenal cortex, adrenocorticotropin hormone (ACTH) and angiotensin II act on their receptors is reviewed, including structure-activity relationships and their potential applications. Particular attention has been given to crucial second messengers and how various kinases, phosphatases, and cytoskeleton-associated proteins interact to ensure homeostasis and/or meet physiological demands. References to animal studies are also made in an attempt to unravel associated clinical conditions. Many of the aspects addressed in this article still represent a challenge for future studies, their outcome aimed at providing evidence that the adrenal gland, through its steroid hormones, occupies a central position in many situations where homeostasis is disrupted, thus highlighting the relevance of exploring and understanding how this key organ is regulated. © 2014 American Physiological Society. Compr Physiol 4:889-964, 2014.
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Affiliation(s)
- Nicole Gallo-Payet
- Division of Endocrinology, Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, and Centre de Recherche Clinique Étienne-Le Bel of the Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada
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27
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黄 锦, 杨 吉, 凌 春, 赵 大, 谢 宇, 由 振. [The mechanism of inhibition effect of adenovirus-mediated ING4 on human lung adenocarcinoma xenografts in nude mice]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014; 17:142-7. [PMID: 24581166 PMCID: PMC6000057 DOI: 10.3779/j.issn.1009-3419.2014.02.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 11/05/2013] [Indexed: 11/05/2022]
Abstract
BACKGROUND AND OBJECTIVE The inhibitor of growth 4 (ING4) is an important tumor suppressive gene.It has been proven that ING4 could inhibite the proliferation of many tumors. e aim of this study is to investigate the inhibitory effect and anti-cancer mechanism of adenovirus-mediated ING4 gene on SPC-A1 human lung adenocarcinoma in nude mice. METHODS A human lung adenocarcinoma xenograft model was established with SPC-A1 cells in nude mice. A total of 15 tumor-bearing nude mice were randomly divided into three groups, namely, PBS, Ad-GFP, and Ad-ING4. e mice in the three groups were intratumorally injected every other day. Their tumor volumes were continually recorded. The treatment tumors were then removed from the mice and weighed. Tumor inhibition rates were calculated. Cell apoptosis was examined by TUNEL method. Caspase-3, COX-2, Fas, and FasL expressions were investigated by immunohistochemistry SP assay. RESULTS Both tumor weight and volume in the Ad-ING4 group were significantly decreased. The tumor inhibition rate of the mice in the Ad-ING4 group (33.17% ± 5.24%) was statistically different from that of the mice in the Ad-GFP group (1.31% ± 0.31%; P<0.05). The apoptotic index of the mice in the Ad-ING4 group (69.23% ± 6.53%) was also significantly different from those in PBS (17.04% ± 1.10%) and Ad-GFP groups (18.81% ± 1.93%; P<0.05). Based on immunohistochemistry SP assay, the results showed that Ad-ING4 may not only upregulate the expressions of caspase-3, Fas, and FasL but also downregulate the expression of COX-2. CONCLUSION ING4 gene elicited a remarkable growth inhibitory e-ect on human lung adenocarcinoma xenografts in nude mice. e mechanism is possibly related to an increase in tumor cell apoptosis.
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Affiliation(s)
- 锦宏 黄
- 215500 常熟，常熟市第二人民医院呼吸内科Department of Respiratory, Second People's Hospital of Changshu, Changshu 215500, China
| | - 吉成 杨
- 215123 苏州，苏州大学医学部基础医学与生物科学学院细胞与分子生物学教研室Department of Cell and Molecular Biology, College of Medicine, Soochow University, Suzhou 215123, China
| | - 春华 凌
- 215006 苏州，苏州大学附属第一医院呼吸内科Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - 大国 赵
- 215006 苏州，苏州大学附属第一医院呼吸内科Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - 宇锋 谢
- 215123 苏州，苏州大学医学部基础医学与生物科学学院细胞与分子生物学教研室Department of Cell and Molecular Biology, College of Medicine, Soochow University, Suzhou 215123, China
| | - 振华 由
- 215500 常熟，常熟市第二人民医院呼吸内科Department of Respiratory, Second People's Hospital of Changshu, Changshu 215500, China
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Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors. Gastric Cancer 2014; 17:87-96. [PMID: 23504291 DOI: 10.1007/s10120-013-0248-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 02/19/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Inhibitor of growth 4 (ING4) has deserved attention as a tumor suppressor gene in many malignant tumors. In our study, we investigated ING4 immunoexpression in gastrointestinal stromal tumors (GISTs) and its prognostic value. METHOD The expression of ING4 and Ki67 was investigated in 41 samples of various risk gastrointestinal stromal tumors by immunohistochemical technique. The associations of ING4 expression and clinicopathological parameters, and prognosis of the patients, were analyzed by multivariate Cox regression analysis. RESULTS ING4 expression showed a decreased trend from lower-risk to high-risk gastrointestinal stromal tumors, and an opposite trend for Ki67 expression. In lower-risk tumors, it was found the expression level of ING4 was 78.95 % ± 27.90 % and that of Ki67 was 4.42 % ± 3.75 %. However, in high-risk tumors, the expression level of ING4 was 9.23 % ± 7.66 % and that of Ki67 was 18.50 % ± 9.09 %. There was a strongly negative correlation between the expression levels of ING4 and Ki67. A significant difference was observed in the expression of ING4 between invasion and non-invasion (p < 0.001). The expression of ING4 was markedly correlated with tumor size (p < 0.001), mitotic index (p < 0.001), tumor necrosis (p = 0.021), invasion (p < 0.001), recurrence and metastasis (p = 0.021), and mortality (p < 0.001). CONCLUSION The low expression level of ING4 protein was correlated with high-risk GISTs. ING4 might be involved in the progression of GISTs and inhibit its invasion. ING4 might be one of the prognostic indicators in GISTs.
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Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. Prog Lipid Res 2013; 52:666-80. [PMID: 24095826 DOI: 10.1016/j.plipres.2013.09.002] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/25/2013] [Accepted: 09/12/2013] [Indexed: 01/31/2023]
Abstract
3β-Hydroxysterol Δ(24)-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol. This ultimate step of cholesterol biosynthesis appears to be remarkable in its diverse functions and the number of diseases it is implicated in from vascular disease to Hepatitis C virus (HCV) infection to cancer to Alzheimer's disease. This review summarizes the present knowledge on the DHCR24 gene, sterol Δ(24)-reductase protein and the regulation of both. In addition, the functions of desmosterol, DHCR24 and their roles in human diseases are discussed. It is apparent that DHCR24 exerts more complex effects than what would be expected based on the enzymatic activity of sterol Δ(24)-reduction alone, such as its influence in modulating oxidative stress. Increasing information about DHCR24 membrane association, processing, enzymatic regulation and interaction partners will provide further fundamental insights into DHCR24 and its many and varied biological roles.
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Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance. Cell Res 2013; 23:1310-21. [PMID: 23896986 DOI: 10.1038/cr.2013.99] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 06/13/2013] [Accepted: 06/26/2013] [Indexed: 12/17/2022] Open
Abstract
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
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Insulin receptor tyrosine kinase substrate activates EGFR/ERK signalling pathway and promotes cell proliferation of hepatocellular carcinoma. Cancer Lett 2013; 337:96-106. [PMID: 23693078 DOI: 10.1016/j.canlet.2013.05.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2013] [Revised: 05/07/2013] [Accepted: 05/14/2013] [Indexed: 11/21/2022]
Abstract
Insulin receptor tyrosine kinase substrate (IRTKS) is closely associated with actin remodelling and membrane protrusion, but its role in the pathogenesis of malignant tumours, including hepatocellular carcinoma (HCC), is still unknown. In this study, we showed that IRTKS was frequently upregulated in HCC samples, and its expression level was significantly associated with tumour size. Enforced expression of IRTKS in human HCC cell lines significantly promoted their proliferation and colony formation in vitro, and their capacity to develop tumour xenografts in vivo, whereas knockdown of IRTKS resulted in the opposite effects. Furthermore, the bromodeoxyuridine (BrdU) incorporation analyses and propidium iodide staining indicated that IRTKS can promote the entry into S phase of cell cycle progression. Significantly, IRTKS can interact with epidermal growth factor receptor (EGFR), results in the phosphorylation of extracellular signal-regulated kinase (ERK). By contrast, inhibition of ERK activation can attenuate the effects of IRTKS overexpression on cellular proliferation. Taken together, these data demonstrate that IRTKS promotes the proliferation of HCC cells by enhancing EGFR-ERK signalling pathway.
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Feng X, Yang R, Zheng X, Zhang F. Identification of a novel nuclear-localized adenylate kinase 6 from Arabidopsis thaliana as an essential stem growth factor. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2012; 61:180-186. [PMID: 23121860 DOI: 10.1016/j.plaphy.2012.10.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2012] [Accepted: 10/04/2012] [Indexed: 05/27/2023]
Abstract
Adenylate kinase (AK; EC 2.7.4.3) is highly conserved across a wide range of organisms, including Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana, and Homo sapiens. While AK6 orthologs play important roles in the growth of yeast and worms, the physiological function of AK6 in A. thaliana is still unknown. In this study, we first cloned and expressed Arabidopsis adenylate kinase 6 (AAK6). Enzyme assays revealed that AAK6 has characteristic adenylate kinase properties, with ATP as the preferred phosphate donor and AMP as the best phosphate acceptor. A subcellular localization assay demonstrated that AAK6 had a predominant nuclear localization. Through biochemical purification and mass spectrometry analysis, a putative homolog of the S. cerevisiae Rps14 protein was identified as a partner of AAK6. Most importantly, we observed that aak6 T-DNA insertion mutants had decreased stem growth compared with wild-type plants. These data indicate that AAK6 exhibits adenylate kinase activity and is an essential growth factor in Arabidopsis.
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Affiliation(s)
- Xue Feng
- Capital Normal University Affiliated Li Ze Middle School, Beijing 100071, China
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Milnthorpe AT, Soloviev M. The use of EST expression matrixes for the quality control of gene expression data. PLoS One 2012; 7:e32966. [PMID: 22412959 PMCID: PMC3297614 DOI: 10.1371/journal.pone.0032966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 02/06/2012] [Indexed: 01/10/2023] Open
Abstract
EST expression profiling provides an attractive tool for studying differential gene expression, but cDNA libraries' origins and EST data quality are not always known or reported. Libraries may originate from pooled or mixed tissues; EST clustering, EST counts, library annotations and analysis algorithms may contain errors. Traditional data analysis methods, including research into tissue-specific gene expression, assume EST counts to be correct and libraries to be correctly annotated, which is not always the case. Therefore, a method capable of assessing the quality of expression data based on that data alone would be invaluable for assessing the quality of EST data and determining their suitability for mRNA expression analysis. Here we report an approach to the selection of a small generic subset of 244 UniGene clusters suitable for identification of the tissue of origin for EST libraries and quality control of the expression data using EST expression information alone. We created a small expression matrix of UniGene IDs using two rounds of selection followed by two rounds of optimisation. Our selection procedures differ from traditional approaches to finding "tissue-specific" genes and our matrix yields consistency high positive correlation values for libraries with confirmed tissues of origin and can be applied for tissue typing and quality control of libraries as small as just a few hundred total ESTs. Furthermore, we can pick up tissue correlations between related tissues e.g. brain and peripheral nervous tissue, heart and muscle tissues and identify tissue origins for a few libraries of uncharacterised tissue identity. It was possible to confirm tissue identity for some libraries which have been derived from cancer tissues or have been normalised. Tissue matching is affected strongly by cancer progression or library normalisation and our approach may potentially be applied for elucidating the stage of normalisation in normalised libraries or for cancer staging.
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Affiliation(s)
- Andrew T. Milnthorpe
- School of Biological Sciences, CBMS, Royal Holloway University of London, Egham, Surrey, United Kingdom
| | - Mikhail Soloviev
- School of Biological Sciences, CBMS, Royal Holloway University of London, Egham, Surrey, United Kingdom
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Thyroid paraganglioma. Report of 3 cases and description of an immunohistochemical profile useful in the differential diagnosis with medullary thyroid carcinoma, based on complementary DNA array results. Hum Pathol 2011; 43:1103-12. [PMID: 22209341 DOI: 10.1016/j.humpath.2011.08.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Revised: 08/12/2011] [Accepted: 08/18/2011] [Indexed: 11/24/2022]
Abstract
Thyroid paraganglioma is a rare disorder that sometimes poses problems in differential diagnosis with medullary thyroid carcinoma. So far, differential diagnosis is solved with the help of some markers that are frequently expressed in medullary thyroid carcinoma (thyroid transcription factor 1, calcitonin, and carcinoembryonic antigen). However, some of these markers are not absolutely specific of medullary thyroid carcinoma and may be expressed in other tumors. Here we report 3 new cases of thyroid paraganglioma and describe our strategy to design a diagnostic immunohistochemical battery. First, we performed a comparative analysis of the expression profile of head and neck paragangliomas and medullary thyroid carcinoma, obtained after complementary DNA array analysis of 2 series of fresh-frozen samples of paragangliomas and medullary thyroid carcinoma, respectively. Seven biomarkers showing differential expression were selected (nicotinamide adenine dinucleotide dehydrogenase 1 alpha subcomplex, 4-like 2, NDUFA4L2; cytochrome c oxidase subunit IV isoform 2; vesicular monoamine transporter 2; calcitonin gene-related protein/calcitonin; carcinoembryonic antigen; and thyroid transcription factor 1) for immunohistochemical analysis. Two tissue microarrays were constructed from 2 different series of paraffin-embedded samples of paragangliomas and medullary thyroid carcinoma. We provide a classifying rule for differential diagnosis that combines negativity or low staining for calcitonin gene-related protein (histologic score, <10) or calcitonin (histologic score, <50) together with positivity of any of NADH dehydrogenase 1 alpha subcomplex, 4-like 2; cytochrome c oxidase subunit IV isoform 2; or vesicular monoamine transporter 2 to predict paragangliomas, showing a prediction error of 0%. Finally, the immunohistochemical battery was checked in paraffin-embedded blocks from 4 examples of thyroid paraganglioma (1 previously reported case and 3 new cases), showing also a prediction error of 0%. Our results suggest that the comparative expression profile, obtained by complementary DNA arrays, seems to be a good tool to design immunohistochemical batteries used in differential diagnosis.
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35
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The mechanism of mimecan transcription induced by glucocorticoid in pituitary corticotroph cells. Mol Cell Biochem 2011; 360:321-8. [DOI: 10.1007/s11010-011-1071-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 09/08/2011] [Indexed: 10/17/2022]
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Wang X, Liu Y, Yang Z, Zhang Z, Zhou W, Ye Z, Zhang W, Zhang S, Yang Z, Feng X, Chen F, Hu R. Glucose metabolism-related protein 1 (GMRP1) regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway in rats and mice. Diabetologia 2011; 54:852-63. [PMID: 21267538 DOI: 10.1007/s00125-011-2048-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 12/10/2010] [Indexed: 12/31/2022]
Abstract
AIMS/HYPOTHESIS We attempted to elucidate the impacts on and possible mechanisms by which glucose metabolism-related protein 1 (GMRP1) affects beta cell survival. METHODS Adenovirus-mediated GMRP1 overproduction and siRNA-mediated knockdown were performed in INS-1E cells and rat islets, after which cell proliferation or apoptosis were determined, and phosphorylation of Akt and BCL2-associated agonist of cell death (BAD) investigated. INS-1E cells and rat islets were cultured at 5.6 (low) or 25 mmol/l (high) glucose for 24 or 48 h, and cell proliferation or apoptosis and GMRP1 levels were investigated. INS-1E cells were treated for 24 h with 0, 10, 50 and 100 nmol/l insulin, and GMRP1 levels were determined. After INS-1E cells were transfected with siRNA for 72 h, high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation were investigated. Glucose-infused rat models were established and beta cell proliferation and mass were evaluated. Levels of GMRP1, and phosphorylation of Akt and BAD were determined in glucose-infused islets. The GMRP1-mediated Akt pathway was also investigated in db/db mice. RESULTS Overproduction of GMRP1 promoted beta cell proliferation via increased phosphorylation of Akt. Knockdown of Gmrp1 (also known as Btbd10) reduced phosphorylation of Akt with enhanced beta cell apoptosis. High glucose increased GMRP1 levels and cell proliferation in INS-1E cells and islet cells. Knockdown of Gmrp1 decreased high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation. Increased GMRP1 levels were involved in the enhancement of beta cell proliferation and mass in glucose-infused islets. Decreased GMRP1 levels may participate in beta cell apoptosis of db/db mice. CONCLUSIONS/INTERPRETATION GMRP1 regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway.
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Affiliation(s)
- X Wang
- Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Wulumuqi Road Middle, Shanghai 200040, People's Republic of China.
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St-Amand J, Yoshioka M, Tanaka K, Nishida Y. Transcriptome-wide identification of preferentially expressed genes in the hypothalamus and pituitary gland. Front Endocrinol (Lausanne) 2011; 2:111. [PMID: 22649398 PMCID: PMC3355919 DOI: 10.3389/fendo.2011.00111] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Accepted: 12/14/2011] [Indexed: 01/01/2023] Open
Abstract
To identify preferentially expressed genes in the central endocrine organs of the hypothalamus and pituitary gland, we generated transcriptome-wide mRNA profiles of the hypothalamus, pituitary gland, and parietal cortex in male mice (12-15 weeks old) using serial analysis of gene expression (SAGE). Total counts of SAGE tags for the hypothalamus, pituitary gland, and parietal cortex were 165824, 126688, and 161045 tags, respectively. This represented 59244, 45151, and 55131 distinct tags, respectively. Comparison of these mRNA profiles revealed that 22 mRNA species, including three potential novel transcripts, were preferentially expressed in the hypothalamus. In addition to well-known hypothalamic transcripts, such as hypocretin, several genes involved in hormone function, intracellular transduction, metabolism, protein transport, steroidogenesis, extracellular matrix, and brain disease were identified as preferentially expressed hypothalamic transcripts. In the pituitary gland, 106 mRNA species, including 60 potential novel transcripts, were preferentially expressed. In addition to well-known pituitary genes, such as growth hormone and thyroid stimulating hormone beta, a number of genes classified to function in transport, amino acid metabolism, intracellular transduction, cell adhesion, disulfide bond formation, stress response, transcription, protein synthesis, and turnover, cell differentiation, the cell cycle, and in the cytoskeleton and extracellular matrix were also preferentially expressed. In conclusion, the current study identified not only well-known hypothalamic and pituitary transcripts but also a number of new candidates likely to be involved in endocrine homeostatic systems regulated by the hypothalamus and pituitary gland.
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Affiliation(s)
- Jonny St-Amand
- Functional Genomics Laboratory, Department of Anatomy and Physiology, Molecular Endocrinology and Oncology Research Center, Laval University Medical CenterLaval University, QC, Canada
- *Correspondence: Jonny St-Amand, Functional Genomics Laboratory, Department of Anatomy and Physiology, Molecular Endocrinology and Oncology Research Center Laval University Medical Center, Laval University, 2705 Blvd Laurier, Quebec, QC, Canada G1V 4G2. e-mail: ; Yuichiro Nishida, Department of Preventive Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. e-mail:
| | - Mayumi Yoshioka
- Functional Genomics Laboratory, Department of Anatomy and Physiology, Molecular Endocrinology and Oncology Research Center, Laval University Medical CenterLaval University, QC, Canada
| | - Keitaro Tanaka
- Department of Preventive Medicine, Saga UniversitySaga, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Saga UniversitySaga, Japan
- *Correspondence: Jonny St-Amand, Functional Genomics Laboratory, Department of Anatomy and Physiology, Molecular Endocrinology and Oncology Research Center Laval University Medical Center, Laval University, 2705 Blvd Laurier, Quebec, QC, Canada G1V 4G2. e-mail: ; Yuichiro Nishida, Department of Preventive Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. e-mail:
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Tooley CES, Petkowski JJ, Muratore-Schroeder TL, Balsbaugh JL, Shabanowitz J, Sabat M, Minor W, Hunt DF, Macara IG. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein. Nature 2010; 466:1125-8. [PMID: 20668449 PMCID: PMC2939154 DOI: 10.1038/nature09343] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Revised: 08/26/2010] [Accepted: 07/08/2010] [Indexed: 11/16/2022]
Abstract
The post-translational methylation of α-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L331–2, but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be α-N-methylated3–10. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of α-N-methylation has been identified3, 11. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects3, 11, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating they may be targets of the same, unknown enzyme3,12. The initiating Met is cleaved, and the exposed α-amino group is mono-, di-, or trimethylated. Here we report the discovery of the first α-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET/TAF-I/PHAPII and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants3, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.
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Affiliation(s)
- Christine E Schaner Tooley
- Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
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Ma QY, Zuo CL, Ma JH, Zhang XN, Ru Y, Li P, Pan CM, Liu Z, Cao HM, Chen MD, Song HD. Glucocorticoid up-regulates mimecan expression in corticotroph cells. Mol Cell Endocrinol 2010; 321:239-44. [PMID: 20178827 DOI: 10.1016/j.mce.2010.02.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 02/15/2010] [Accepted: 02/16/2010] [Indexed: 11/25/2022]
Abstract
Mimecan is a protein of unknown function that is expressed in the pituitary. The aim of this study is to clarify the regulation and intracellular localisation of mimecan gene expression in the pituitary. With immunohistochemistry, we observed that mimecan protein was co-expressed with ACTH in pituitary corticotroph cells. Northern and Western blot analyses revealed that mimecan expression and secretion in corticotroph cells were up-regulated by treating AtT-20 cells with glucocorticoid. Meanwhile, mimecan expression in rat primary culture pituitary cells was also promoted by glucocorticoid. Co-incubation of AtT-20 cells with RU486 and glucocorticoid completely reversed the induction of mimecan gene expression by glucocorticoid. In addition, luciferase reporter assays showed that the -1474/+43 promoter region of mimecan was sufficient for glucocorticoid-responsive mimecan expression. These data collectively suggest that mimecan expressed in pituitary corticotroph cells is increased by glucocorticoid and that the up-regulation may be mediated by the classical GR pathways.
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Affiliation(s)
- Qin-Yun Ma
- Ruijin Hospital, Shanghai Institute of Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai, China
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Assié G, Guillaud-Bataille M, Ragazzon B, Bertagna X, Bertherat J, Clauser E. The pathophysiology, diagnosis and prognosis of adrenocortical tumors revisited by transcriptome analyses. Trends Endocrinol Metab 2010; 21:325-34. [PMID: 20097573 DOI: 10.1016/j.tem.2009.12.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Revised: 12/15/2009] [Accepted: 12/18/2009] [Indexed: 11/24/2022]
Abstract
Analyzing gene expression (transcriptome) in tissue is now reliable using industrial pangenomic microarrays. Accumulating data on adrenal cortex and adrenocortical tumor transcriptomes have already identified striking transcriptome differences not only between adenoma and carcinoma but also between two sets of carcinoma, which have very different prognoses. These findings result in the development of diagnostic and prognostic molecular predictors, which improve the outcome determination compared with standard clinical and pathological tools. These transcriptome data observing adrenocortical tumor phenotype in great but complex detail, combined with genomic and proteomic information, will function for future research investigating the pathophysiology of their tumorigenesis and hormonal secretion.
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Affiliation(s)
- Guillaume Assié
- Department of Endocrinology, Metabolism and Cancer, Institut Cochin, INSERM U567, University Paris Descartes, CNRS UMR8104, Paris, France
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Miranda KC, Karet FE, Brown D. An extended nomenclature for mammalian V-ATPase subunit genes and splice variants. PLoS One 2010; 5:e9531. [PMID: 20224822 PMCID: PMC2835735 DOI: 10.1371/journal.pone.0009531] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Accepted: 02/03/2010] [Indexed: 12/31/2022] Open
Abstract
The vacuolar-type H(+)-ATPase (V-ATPase) is a multisubunit proton pump that is involved in both intra- and extracellular acidification processes throughout the body. Multiple homologs and splice variants of V-ATPase subunits are thought to explain its varied spatial and temporal expression pattern in different cell types. Recently subunit nomenclature was standardized with a total of 22 subunit variants identified. However this standardization did not accommodate the existence of splice variants and is therefore incomplete. Thus, we propose here an extension of subunit nomenclature along with a literature and sequence database scan for additional V-ATPase subunits. An additional 17 variants were pulled from a literature search while 4 uncharacterized potential subunit variants were found in sequence databases. These findings have been integrated with the current V-ATPase knowledge base to create a new V-ATPase subunit catalogue. It is envisioned this catalogue will form a new platform on which future studies into tissue- and organelle-specific V-ATPase expression, localization and function can be based.
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Affiliation(s)
- Kevin C. Miranda
- Program in Membrane Biology and Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Fiona E. Karet
- Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Dennis Brown
- Program in Membrane Biology and Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
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Wang X, Jiang H, Zhou W, Zhang Z, Yang Z, Lu Y, Lu B, Wang X, Ding Q, Hu R. Molecular cloning of a novel nuclear factor, TDRP1, in spermatogenic cells of testis and its relationship with spermatogenesis. Biochem Biophys Res Commun 2010; 394:29-35. [PMID: 20170638 DOI: 10.1016/j.bbrc.2010.02.061] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Accepted: 02/11/2010] [Indexed: 10/19/2022]
Abstract
We reported the identification of a novel gene termed TDRP (encoding testis development-related protein) that might be involved in spermatogenesis. The human TDRP gene had two distinct transcripts, TDRP1 and TDRP2, which encoded proteins of 183 aa and 198 aa respectively. Tdrp mRNA was predominantly expressed in testis tissue. We generated rabbit polyclonal antibodies specific against human TDRP1. Immunohistochemistry analysis showed TDRP1 was expressed in spermatogenic cells, especially with high expression in spermatocytes. We provided evidence that TDRP1 distributed in both cytoplasm and nuclei of spermatogenic cells. Expression patterns of Tdrp1 mRNA and its protein were investigated in the rat testis tissues of different developmental stages. Both Tdrp1 mRNA and its protein were barely detected in the testis of neonatal rats, increased remarkably at 3weeks postpartum, and peaked at 2months postpartum. We also investigated TDRP1 expressions in testis tissues of azoospermic men with defective spermatogenesis. Western blot analysis showed that TDRP1 expressions were significantly lower in the testis tissues of azoospermic men compared with normal controls. These current data demonstrated that as a nuclear factor, TDRP1 might play an important role in spermatogenesis.
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Affiliation(s)
- Xuanchun Wang
- Department of Endocrinology, Huashan Hospital, Institute of Endocrinology and Diabetology at Fudan University, Shanghai Medical College, Fudan University, Shanghai 200040, China
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Battista MC, Roberge C, Martinez A, Gallo-Payet N. 24-dehydrocholesterol reductase/seladin-1: a key protein differentially involved in adrenocorticotropin effects observed in human and rat adrenal cortex. Endocrinology 2009; 150:4180-90. [PMID: 19520779 DOI: 10.1210/en.2009-0410] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
DHCR24 (24-dehydrocholesterol reductase), or seladin-1, is one of the most expressed genes in the adrenal gland. Because the rat and human adult adrenal cortex differ in their respective functional properties, the aim of the present study was to verify whether seladin-1 may be differentially involved in basal and ACTH-stimulated steroidogenesis and oxidative stress management. Seladin-1 expression was predominantly observed in both human and rat zona fasciculata, with a predominant cytoplasmic localization in human cells and a nucleo-cytoplasmic distribution in rat cells. In human fasciculata cells, localization of the protein was primarily associated with the endoplasmic reticulum. Although its expression was increased by ACTH, its intracellular localization was not altered by ACTH treatment (10 nm) or by the seladin-1 inhibitor U18666A (75 nm). Preincubation with U18666A did not modify the ACTH-induced increase in cortisol secretion but abolished the ACTH-induced increase in dehydroepiandrosterone secretion. In rat fasciculata cells, ACTH induced a massive redistribution of seladin-1 from the cytoplasm (cis-Golgi apparatus) to the nucleus, which was inhibited by preincubation with U18666A. Preincubation with U18666A also decreased ACTH-induced seladin-1 and 11beta-hydroxylase protein expression as well as corticosterone production, increased ACTH-induced ROS production but decreased ACTH-induced expression of the detoxifying protein aldo-ketoreductase 1b7. Thus, protection against acutely elevated ACTH-induced oxidative stress in rat fasciculata cells is correlated with nuclear relocalization of seladin-1 and its effects on cellular detoxifying machinery. Altogether, these results indicate that seladin-1 expression and intracellular localization are correlated with both the intensity and nature of ACTH-induced steroidogenesis and resultant oxidative stress.
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Affiliation(s)
- Marie-Claude Battista
- Service d'Endocrinologie, Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Depletion of tubulin polymerization promoting protein family member 3 suppresses HeLa cell proliferation. Mol Cell Biochem 2009; 333:91-8. [PMID: 19633818 DOI: 10.1007/s11010-009-0208-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2009] [Accepted: 07/06/2009] [Indexed: 10/20/2022]
Abstract
Microtubules (MTs) play an important role in cell division, and their functions are regulated by a set of microtubule-associated proteins (MAPs). Tubulin polymerization promoting protein family member 3 (TPPP3), also known as p20, is a new member of the tubulin polymerization promoting protein (TPPP) family. Previous studies have demonstrated that TPPP3 specifically binds to MTs and positively regulates MTs assembly, which leads to significant ultrastructural alterations of the MTs network. However, the physiological function of TPPP3 is still largely unknown. In the present study, we showed that knockdown of endogenous TPPP3 by RNA interference (RNAi) suppressed cell proliferation and induced cell cycle arrest in HeLa cells. Furthermore, we showed that the depletion of TPPP3 caused mitotic abnormalities, such as the formation of multipolar spindles and chromosome segregation errors, which lead to apoptosis in HeLa cells. Our study suggested that TPPP3 played a crucial role in cell mitosis by regulating centrosomes amplification and/or spindles translocation processes.
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[Gene profiling and classification of adrenocortical tumors]. ANNALES D'ENDOCRINOLOGIE 2009; 70:186-91. [PMID: 19296923 DOI: 10.1016/j.ando.2009.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Ma Y, Qi X, Du J, Song S, Feng D, Qi J, Zhu Z, Zhang X, Xiao H, Han Z, Hao X. Identification of candidate genes for human pituitary development by EST analysis. BMC Genomics 2009; 10:109. [PMID: 19284880 PMCID: PMC2664823 DOI: 10.1186/1471-2164-10-109] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Accepted: 03/15/2009] [Indexed: 11/29/2022] Open
Abstract
Background The pituitary is a critical neuroendocrine gland that is comprised of five hormone-secreting cell types, which develops in tandem during the embryonic stage. Some essential genes have been identified in the early stage of adenohypophysial development, such as PITX1, FGF8, BMP4 and SF-1. However, it is likely that a large number of signaling molecules and transcription factors essential for determination and terminal differentiation of specific cell types remain unidentified. High-throughput methods such as microarray analysis may facilitate the measurement of gene transcriptional levels, while Expressed sequence tag (EST) sequencing, an efficient method for gene discovery and expression level analysis, may no-redundantly help to understand gene expression patterns during development. Results A total of 9,271 ESTs were generated from both fetal and adult pituitaries, and assigned into 961 gene/EST clusters in fetal and 2,747 in adult pituitary by homology analysis. The transcription maps derived from these data indicated that developmentally relevant genes, such as Sox4, ST13 and ZNF185, were dominant in the cDNA library of fetal pituitary, while hormones and hormone-associated genes, such as GH1, GH2, POMC, LHβ, CHGA and CHGB, were dominant in adult pituitary. Furthermore, by using RT-PCR and in situ hybridization, Sox4 was found to be one of the main transcription factors expressed in fetal pituitary for the first time. It was expressed at least at E12.5, but decreased after E17.5. In addition, 40 novel ESTs were identified specifically in this tissue. Conclusion The significant changes in gene expression in both tissues suggest a distinct and dynamic switch between embryonic and adult pituitaries. All these data along with Sox4 should be confirmed to further understand the community of multiple signaling pathways that act as a cooperative network that regulates maturation of the pituitary. It was also suggested that EST sequencing is an efficient means of gene discovery.
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Affiliation(s)
- Yueyun Ma
- Center for Clinical Laboratory Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.
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Maruyama Y, Wakamatsu A, Kawamura Y, Kimura K, Yamamoto JI, Nishikawa T, Kisu Y, Sugano S, Goshima N, Isogai T, Nomura N. Human Gene and Protein Database (HGPD): a novel database presenting a large quantity of experiment-based results in human proteomics. Nucleic Acids Res 2009; 37:D762-6. [PMID: 19073703 PMCID: PMC2686585 DOI: 10.1093/nar/gkn872] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Completion of human genome sequencing has greatly accelerated functional genomic research. Full-length cDNA clones are essential experimental tools for functional analysis of human genes. In one of the projects of the New Energy and Industrial Technology Development Organization (NEDO) in Japan, the full-length human cDNA sequencing project (FLJ project), nucleotide sequences of approximately 30 000 human cDNA clones have been analyzed. The Gateway system is a versatile framework to construct a variety of expression clones for various experiments. We have constructed 33 275 human Gateway entry clones from full-length cDNAs, representing to our knowledge the largest collection in the world. Utilizing these clones with a highly efficient cell-free protein synthesis system based on wheat germ extract, we have systematically and comprehensively produced and analyzed human proteins in vitro. Sequence information for both amino acids and nucleotides of open reading frames of cDNAs cloned into Gateway entry clones and in vitro expression data using those clones can be retrieved from the Human Gene and Protein Database (HGPD, http://www.HGPD.jp). HGPD is a unique database that stores the information of a set of human Gateway entry clones and protein expression data and helps the user to search the Gateway entry clones.
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Affiliation(s)
- Yukio Maruyama
- Japan Biological Informatics Consortium, Aomi, Koto-ku, Tokyo 135-8073, Japan
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Federovitch CM, Jones YZ, Tong AH, Boone C, Prinz WA, Hampton RY. Genetic and structural analysis of Hmg2p-induced endoplasmic reticulum remodeling in Saccharomyces cerevisiae. Mol Biol Cell 2008; 19:4506-20. [PMID: 18667535 DOI: 10.1091/mbc.e07-11-1188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The endoplasmic reticulum (ER) is highly plastic, and increased expression of distinct single ER-resident membrane proteins, such as HMG-CoA reductase (HMGR), can induce a dramatic restructuring of ER membranes into highly organized arrays. Studies on the ER-remodeling behavior of the two yeast HMGR isozymes, Hmg1p and Hmg2p, suggest that they could be mechanistically distinct. We examined the features of Hmg2p required to generate its characteristic structures, and we found that the molecular requirements are similar to those of Hmg1p. However, the structures generated by Hmg1p and Hmg2p have distinct cell biological features determined by the transmembrane regions of the proteins. In parallel, we conducted a genetic screen to identify HER genes (required for Hmg2p-induced ER Remodeling), further confirming that the mechanisms of membrane reorganization by these two proteins are distinct because most of the HER genes were required for Hmg2p but not Hmg1p-induced ER remodeling. One of the HER genes identified was PSD1, which encodes the phospholipid biosynthetic enzyme phosphatidylserine decarboxylase. This direct connection to phospholipid biosynthesis prompted a more detailed examination of the effects of Hmg2p on phospholipid mutants and composition. Our analysis revealed that overexpression of Hmg2p caused significant and specific growth defects in nulls of the methylation pathway for phosphatidylcholine biosynthesis that includes the Psd1p enzyme. Furthermore, increased expression of Hmg2p altered the composition of cellular phospholipids in a manner that implied a role for PSD1. These phospholipid effects, unlike Hmg2p-induced ER remodeling, required the enzymatic activity of Hmg2p. Together, our results indicate that, although related, Hmg2p- and Hmg1p-induced ER remodeling are mechanistically distinct.
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Affiliation(s)
- Christine M Federovitch
- UCSD Division of Biological Sciences, Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093-0347, USA
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Stratakis CA, Horvath A. How the new tools to analyze the human genome are opening new perspectives: the use of gene expression in investigations of the adrenal cortex. ANNALES D'ENDOCRINOLOGIE 2008; 69:123-9. [PMID: 18423555 DOI: 10.1016/j.ando.2008.02.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
With the promise of state-of-the-art molecular technologies and the tools provided by the human genome project, a number of investigators are trying to identify molecular targets of adrenocortical tumorigenesis. One path in this endeavor was the identification by positional cloning of genes that are mutated in rare adrenocortical tumors. The subject of this article is an update of the results of experiments in the second path that was followed by us and others: that of using genome-wide expression analysis of adrenocortical cells in normal and various disease states. Transcriptomic analysis is a rapidly evolving technology; this article summarizes some data on the adrenal cortex and points out how these new technologies can be used in the identification of important genes and molecular pathways in both normal and diseased adrenal cortex.
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Affiliation(s)
- C A Stratakis
- Section on Endocrinology, Genetics, Program on Developmental Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1862, USA.
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Otis M, Battista MC, Provencher M, Campbell S, Roberge C, Payet MD, Gallo-Payet N. From integrative signalling to metabolic disorders. J Steroid Biochem Mol Biol 2008; 109:224-9. [PMID: 18468884 DOI: 10.1016/j.jsbmb.2008.03.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The adrenal cortex undergoes constant dynamic structural changes, a key element in ensuring integrative functionality of the gland. Studies have shown that the cellular environment can modulate cell functions such as proliferation and steroid secretion. For example, 3-day treatment with angiotensin II promotes protein synthesis with a concomitant decrease in proliferation of glomerulosa cells, when cultured on fibronectin, but not on collagen IV or laminin. These effects involve close interaction between cytoskeleton-associated proteins and activation of p42/p44mapk and p38 MAPK pathways. On the other hand, adrenocorticotropin hormone (ACTH), which is clearly the most potent stimulus of fasciculata cells, induces specific modulation of targeted proteins, when cells are cultured on collagen IV, but not on fibronectin or laminin. In particular, ACTH treatment leads to increased expression of Seladin-1 and induces the relocalization of Seladin-1 from the cytoplasm to the nucleus, both in vivo and in culture conditions, in adult rats and in human fetal adrenal glands. As a whole, these results indicate that Seladin-1, together with collagen IV, is able to modulate ACTH responsiveness. Hence, Seladin-1 may participate in the regulation of steroidogenesis when localized in the cytoplasm, while conversely protecting cells against oxidative stress generated by intense ACTH stimulation when massively localized in the nucleus.
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Affiliation(s)
- Mélissa Otis
- Service of Endocrinology, Department of Medicine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4
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