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1
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Lin XY, Chu Y, Zhang GS, Zhang HL, Kang K, Wu MX, Zhu J, Xu CS, Lin JX, Huang CK, Chai DJ. Retinoid X receptor agonists alleviate fibroblast activation and post-infarction cardiac remodeling via inhibition of TGF-β1/Smad pathway. Life Sci 2023; 329:121936. [PMID: 37453576 DOI: 10.1016/j.lfs.2023.121936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/10/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-β1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-β1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-β1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-β1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-β1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-β1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-β1/Smad pathway activation.
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Affiliation(s)
- Xiao-Yan Lin
- Ultrasonography Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yong Chu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Guo-Shan Zhang
- Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China
| | - Hai-Lin Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Kai Kang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Min-Xia Wu
- Electron Microscopy Laboratory of Public Technology Service Center, Fujian Medical University, Fuzhou 350004, China
| | - Jiang Zhu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Chang-Sheng Xu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Jin-Xiu Lin
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Chun-Kai Huang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Da-Jun Chai
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China; Cardiovascular Department, National Regional Medical Center, Binhai Branch of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
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2
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Szczepanski HE, Flannigan KL, Mainoli B, Alston L, Baruta GM, Lee JW, Venu VKP, Shearer J, Dufour A, Hirota SA. NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling. FASEB J 2022; 36:e22609. [PMID: 36250380 DOI: 10.1096/fj.202101817rr] [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: 12/01/2021] [Revised: 09/16/2022] [Accepted: 09/30/2022] [Indexed: 11/11/2022]
Abstract
Stricture formation is a common complication of Crohn's disease (CD), driven by enhanced deposition of extracellular matrix (ECM) and expansion of the intestinal smooth muscle layers. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor that exhibits anti-proliferative effects in smooth muscle cells (SMCs). We hypothesized that NR4A1 regulates intestinal SMC proliferation and muscle thickening in the context of inflammation. Intestinal SMCs isolated from Nr4a1+/+ and Nr4a1-/- littermates were subjected to shotgun proteomic analysis, proliferation, and bioenergetic assays. Proliferation was assessed in the presence and absence of NR4A1 agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). In vivo, we compared colonic smooth muscle thickening in Nr4a1+/+ and Nr4a1-/- mice using the chronic dextran sulfate sodium (DSS) model of colitis. Second, SAMP1/YitFc mice (a model of spontaneous ileitis) were treated with Csn-B and small intestinal smooth muscle thickening was assessed. SMCs isolated from Nr4a1-/- mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1+/+ SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1-/- mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1-/- mice exhibited increased colonic smooth muscle thickness following repeated cycles of DSS. Activating NR4A1 with Csn-B, in the context of established inflammation, reduced ileal smooth muscle thickening in SAMP1/YitFc mice. Targeting NR4A1 may provide a novel approach to regulate intestinal SMC phenotype, limiting excessive proliferation that contributes to stricture development in CD.
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Affiliation(s)
- Holly E Szczepanski
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Kyle L Flannigan
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Barbara Mainoli
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Laurie Alston
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Grace M Baruta
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Joshua W Lee
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Vivek Krishna Pulakazhi Venu
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Jane Shearer
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Antoine Dufour
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.,McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.,Department of Immunology, Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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3
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Leal AS, Reich LA, Moerland JA, Zhang D, Liby KT. Potential therapeutic uses of rexinoids. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2021; 91:141-183. [PMID: 34099107 DOI: 10.1016/bs.apha.2021.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of nuclear receptors, particularly retinoid X receptors (RXR), and their involvement in numerous pathways related to development sparked interest in their immunomodulatory properties. Genetic models using deletion or overexpression of RXR and the subsequent development of several small molecules that are agonists or antagonists of this receptor support a promising therapeutic role for these receptors in immunology. Bexarotene was approved in 1999 for the treatment of cutaneous T cell lymphoma. Several other small molecule RXR agonists have since been synthesized with limited preclinical development, but none have yet achieved FDA approval. Cancer treatment has recently been revolutionized with the introduction of immune checkpoint inhibitors, but their success has been restricted to a minority of patients. This review showcases the emerging immunomodulatory effects of RXR and the potential of small molecules that target this receptor as therapies for cancer and other diseases. Here we describe the essential roles that RXR and partner receptors play in T cells, dendritic cells, macrophages and epithelial cells, especially within the tumor microenvironment. Most of these effects are site and cancer type dependent but skew immune cells toward an anti-inflammatory and anti-tumor effect. This beneficial effect on immune cells supports the promise of combining rexinoids with approved checkpoint blockade therapies in order to enhance efficacy of the latter and to delay or potentially eliminate drug resistance. The data compiled in this review strongly suggest that targeting RXR nuclear receptors is a promising new avenue in immunomodulation for cancer and other chronic inflammatory diseases.
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Affiliation(s)
- Ana S Leal
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Lyndsey A Reich
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Jessica A Moerland
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Di Zhang
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States
| | - Karen T Liby
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, United States.
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Costantini L, Molinari R, Farinon B, Merendino N. Retinoic Acids in the Treatment of Most Lethal Solid Cancers. J Clin Med 2020; 9:E360. [PMID: 32012980 PMCID: PMC7073976 DOI: 10.3390/jcm9020360] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.
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Affiliation(s)
- Lara Costantini
- Department of Ecological and Biological Sciences (DEB), Tuscia University, Largo dell’Università snc, 01100 Viterbo, Italy
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de Almeida NR, Conda-Sheridan M. A review of the molecular design and biological activities of RXR agonists. Med Res Rev 2019; 39:1372-1397. [PMID: 30941786 DOI: 10.1002/med.21578] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 03/09/2019] [Accepted: 03/16/2019] [Indexed: 12/13/2022]
Abstract
An attractive approach to combat disease is to target theregulation of cell function. At the heart of this task are nuclear receptors (NRs); which control functions such as gene transcription. Arguably, the key player in this regulatory machinery is the retinoid X receptor (RXR). This NR associates with a third of the NRs found in humans. Scientists have hypothesized that controlling the activity of RXR is an attractive approach to control cellular functions that modulate diseases such as cancer, diabetes, Alzheimer's disease and Parkinson's disease. In this review, we will describe the key features of the RXR, present a historic perspective of the first RXR agonists, and discuss various templates that have been reported to activate RXR with a focus on their molecular structure, biological activity, and limitations. Finally, we will present an outlook of the field and future directions and considerations to synthesize or modulate RXR agonists to make these compounds a clinical reality.
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Affiliation(s)
| | - Martin Conda-Sheridan
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
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Bouriez D, Giraud J, Gronnier C, Varon C. Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review. Int J Mol Sci 2018; 19:ijms19113388. [PMID: 30380687 PMCID: PMC6275086 DOI: 10.3390/ijms19113388] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/26/2018] [Accepted: 10/26/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new targeted therapies. Those CSCs express biomarkers such as cluster of differentiation 44 (CD44) and display high aldehyde dehydrogenase activity that converts vitamin A-derived retinal into retinoic acids. All-trans retinoic acid (ATRA), which has pro-differentiating properties, has revolutionized the prognosis of acute promyelotic leukemia by increasing its remission rate from 15% to 85%. Recent studies have started to show that ATRA also has an anti-tumoral role on solid cancers such as GC. The purpose of this review is therefore to summarize the work that evaluated the effects of ATRA in GC and to evaluate whether its anti-cancerous action involves gastric CSCs targeting. It has been demonstrated that ATRA can block the cell cycle, enhance apoptosis, and decrease gastric CSCs properties in GC cell lines, tumorspheres, and patient-derived xenograft mice models. Therefore, retinoids and new synthetic retinoids seem to be a promising step forward in targeted therapy of gastric CSC in combination with existing chemotherapies. Future studies should probably focus on these points.
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Affiliation(s)
- Damien Bouriez
- INSERM, U1053, Bordeaux Research in Translational Oncology, 33000 Bordeaux, France.
- Department of Digestive Surgery, Haut-Lévêque Hospital, 33000 Bordeaux, France.
| | - Julie Giraud
- INSERM, U1053, Bordeaux Research in Translational Oncology, 33000 Bordeaux, France.
- Department of Life and Health Sciences, University of Bordeaux, 33000 Bordeaux, France.
| | - Caroline Gronnier
- INSERM, U1053, Bordeaux Research in Translational Oncology, 33000 Bordeaux, France.
- Department of Digestive Surgery, Haut-Lévêque Hospital, 33000 Bordeaux, France.
- Department of Life and Health Sciences, University of Bordeaux, 33000 Bordeaux, France.
| | - Christine Varon
- INSERM, U1053, Bordeaux Research in Translational Oncology, 33000 Bordeaux, France.
- Department of Life and Health Sciences, University of Bordeaux, 33000 Bordeaux, France.
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7
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Chen L, Wu L, Zhu L, Zhao Y. Overview of the structure-based non-genomic effects of the nuclear receptor RXRα. Cell Mol Biol Lett 2018; 23:36. [PMID: 30093910 PMCID: PMC6080560 DOI: 10.1186/s11658-018-0103-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/27/2018] [Indexed: 12/12/2022] Open
Abstract
The nuclear receptor RXRα (retinoid X receptor-α) is a transcription factor that regulates the expression of multiple genes. Its non-genomic function is largely related to its structure, polymeric forms and modification. Previous research revealed that some non-genomic activity of RXRα occurs via formation of heterodimers with Nur77. RXRα-Nur77 heterodimers translocate from the nucleus to the mitochondria in response to certain apoptotic stimuli and this activity correlates with cell apoptosis. More recent studies revealed a significant role for truncated RXRα (tRXRα), which interacts with the p85α subunit of the PI3K/AKT signaling pathway, leading to enhanced activation of AKT and promoting cell growth in vitro and in animals. We recently reported on a series of NSAID sulindac analogs that can bind to tRXRα through a unique binding mechanism. We also identified one analog, K-80003, which can inhibit cancer cell growth by inducing tRXRα to form a tetramer, thus disrupting p85α-tRXRα interaction. This review analyzes the non-genomic effects of RXRα in normal and tumor cells, and discusses the functional differences based on RXRα protein structure (structure source: the RCSB Protein Data Bank).
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Affiliation(s)
- Liqun Chen
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108 China
| | - Lingjuan Wu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108 China
| | - Linyan Zhu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108 China
| | - Yiyi Zhao
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108 China
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8
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Tecalco-Cruz AC. Molecular pathways involved in the transport of nuclear receptors from the nucleus to cytoplasm. J Steroid Biochem Mol Biol 2018; 178:36-44. [PMID: 29107180 DOI: 10.1016/j.jsbmb.2017.10.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/18/2017] [Accepted: 10/25/2017] [Indexed: 12/30/2022]
Abstract
Nuclear receptors (NRs) are transcription regulators that direct the expression of many genes linked to cellular processes, such as proliferation, differentiation, and apoptosis. Additionally, some cellular events are also modulated by signaling pathways induced by NRs outside of the nucleus. Hence, the subcellular transport of NRs is dynamic and is modulated by several signals, protein-protein interactions, and posttranslational modifications. Particularly, the exit of NRs from the nucleus to cytoplasm and/or other compartments is transcendental, as it is this export event, which determines their abundance in the cells' compartments, the activation or attenuation of nuclear or extranuclear pathways, and the magnitude and duration of their effects inside or outside of the nucleus. Consequently, an adequate control of the distribution of NRs is critical for homeostasis, because a deregulation in the nucleo-cytoplasmic transport of NRs could be involved in diseases including cancer as well as metabolic and vascular alterations. In this review, we investigated the pathways and molecular and biological aspects that have been described for the nuclear export of NRs so far and their functional relevance in some diseases. This information suggests that the transport of NRs out of the nucleus is a key mechanism for the identification of new therapeutic targets for alterations associated with the deregulation of the function of NRs.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Programa de Investigación de Cáncer de Mama, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apdo Postal, D.F. 04510, Mexico.
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Wang C, He H, Dou G, Li J, Zhang X, Jiang M, Li P, Huang X, Chen H, Li L, Yang D, Qi H. Ginsenoside 20(S)-Rh2 Induces Apoptosis and Differentiation of Acute Myeloid Leukemia Cells: Role of Orphan Nuclear Receptor Nur77. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:7687-7697. [PMID: 28793767 DOI: 10.1021/acs.jafc.7b02299] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Ginsenoside 20(S)-Rh2 has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. In our study, 20(S)-Rh2 induced the expression of orphan nuclear receptor Nur77 and death receptor proteins Fas, FasL, DR5, and TRAIL, as well as the cleavage of caspase 8 and caspase 3 in HL-60 cells. Importantly, shNur77 attenuated 20(S)-Rh2-induced apoptosis and Fas and DR5 expression. Meanwhile, 20(S)-Rh2 promoted Nur77 translocation from the nucleus to mitochondria and enhanced the interaction between Nur77 and Bcl-2, resulting in the exposure of the BH3 domain of Bcl-2 and activation of Bax. Furthermore, 20(S)-Rh2 promoted the differentiation of HL-60 cells as evidenced by Wright-Giemsa staining, NBT reduction assay, and detection of the myeloid differentiation marker CD11b by flow cytometry. Notably, shNur77 reversed 20(S)-Rh2-mediated HL-60 differentiation. Additionally, 20(S)-Rh2 also exhibited an antileukemic effect and induced Nur77 expression in NOD/SCID mice with the injection of HL-60 cells into the tail vein. Together, our studies suggest that the Nur77-mediated signaling pathway is highly involved in 20(S)-Rh2-induced apoptosis and differentiation of AML cells.
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MESH Headings
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Caspase 3/genetics
- Caspase 3/metabolism
- Caspase 8/genetics
- Caspase 8/metabolism
- Cell Differentiation/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Ginsenosides/pharmacology
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/physiopathology
- Mice
- Mice, Nude
- Mice, SCID
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
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Affiliation(s)
- Chengqiang Wang
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
| | - Hui He
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
| | - Guojun Dou
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
| | - Juan Li
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
| | - Xiaomei Zhang
- Chongqing Academy of Chinese Materia Medica , 34 Nanshan Road, Nan'an District, Chongqing 400065, China
| | - Mingdong Jiang
- Radiotherapy Department, Chongqing Ninth People's Hospital , Jialing Village 69, Beibei District, Chongqing 400700, China
| | - Pan Li
- Radiotherapy Department, Chongqing Ninth People's Hospital , Jialing Village 69, Beibei District, Chongqing 400700, China
| | - Xiaobo Huang
- Radiotherapy Department, Chongqing Ninth People's Hospital , Jialing Village 69, Beibei District, Chongqing 400700, China
| | - Hongxi Chen
- Radiotherapy Department, Chongqing Ninth People's Hospital , Jialing Village 69, Beibei District, Chongqing 400700, China
| | - Li Li
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
| | - Dajian Yang
- Chongqing Academy of Chinese Materia Medica , 34 Nanshan Road, Nan'an District, Chongqing 400065, China
| | - Hongyi Qi
- College of Pharmaceutical Sciences, Southwest University , 2 Tiansheng Road, Beibei District, Chongqing 400716, China
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10
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Cheng B, Al-Shammari FH, Ghader IA, Sequeira F, Thakkar J, Mathew TC. Fundamental studies of adrenal retinoid-X-receptor: Protein isoform, tissue expression, subcellular distribution, and ligand availability. J Steroid Biochem Mol Biol 2017; 171:110-120. [PMID: 28267642 DOI: 10.1016/j.jsbmb.2017.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/14/2017] [Accepted: 03/02/2017] [Indexed: 11/21/2022]
Abstract
Adrenal gland reportedly expresses many nuclear receptors that are known to heterodimerize with retinoid-X-receptor (RXR) for functions, but the information regarding the glandular RXR is not adequate. Studies of rat adrenal homogenate by Western blotting revealed three RXR proteins: RXRα (55kDa), RXRβ (47kDa) and RXR (56kDa). RXRγ was not detectable. After fractionation, RXRα was almost exclusively localized in the nuclear fraction. In comparison, substantial portions of RXRβ and RXR were found in both nuclear and post-nuclear particle fractions, suggesting genomic and non-genomic functions. Cells immunostained for RXRα were primarily localized in zona fasciculata (ZF) and medulla, although some stained cells were found in zona glomerulosa (ZG) and zona reticularis (ZR). In contrast, cells immunostained for RXRβ were concentrated principally in ZG, although some stained cells were seen in ZR, ZF, and medulla (in descending order, qualitatively). Analysis of adrenal lipid extracts by LC/MS did not detect 9-cis-retinoic acid (a potent RXR-ligand) but identified all-trans retinoic acid. Since C20 and C22 polyunsaturated fatty acids (PUFAs) can also activate RXR, subcellular availabilities of unesterified fatty acids were investigated by GC/MS. As results, arachidonic acid (C20:4), adrenic acid (C22:4), docosapentaenoic acid (C22:5), and cervonic acid (C22:6) were detected in the lipids extracted from each subcellular fraction. Thus, the RXR-agonizing PUFAs are available in all the main subcellular compartments considerably. The present findings not only shed light on the adrenal network of RXRs but also provide baseline information for further investigations of RXR heterodimers in the regulation of adrenal steroidogenesis.
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Affiliation(s)
- Behling Cheng
- Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait.
| | - Fatema H Al-Shammari
- Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait
| | - Isra'a A Ghader
- Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait
| | - Fatima Sequeira
- Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait
| | - Jitendra Thakkar
- Department of Biochemistry, Faculty of Medicine, Kuwait University Health Science Center, P. O. Box 24923, Safat 13110, Kuwait
| | - Thazhumpal C Mathew
- Department of Medical Laboratory Science, Faculty of Allied Health, Kuwait University Health Science Center, P.O. Box 31470, Sulaibekhat 90805, Kuwait
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11
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Liu Y, Tang J, Gao X, Wang M, Shen J, You X. Effect of retinoid X receptor-α nuclear export inhibition on apoptosis of neurons in vivo and in vitro. Mol Med Rep 2017. [DOI: 10.3892/mmr.2017.6766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Zhang X, Zhou H, Su Y. Targeting truncated RXRα for cancer therapy. Acta Biochim Biophys Sin (Shanghai) 2016; 48:49-59. [PMID: 26494413 DOI: 10.1093/abbs/gmv104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/24/2015] [Indexed: 01/08/2023] Open
Abstract
Retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a well-established drug target, representing one of the most important targets for pharmacologic interventions and therapeutic applications for cancer. However, how RXRα regulates cancer cell growth and how RXRα modulators suppress tumorigenesis are poorly understood. Altered expression and aberrant function of RXRα are implicated in the development of cancer. Previously, several studies had demonstrated the presence of N-terminally truncated RXRα (tRXRα) proteins resulted from limited proteolysis of RXRα in tumor cells. Recently, we discovered that overexpression of tRXRα can promote tumor growth by interacting with tumor necrosis factor-alpha-induced phosphoinositide 3-kinase and NF-κB signal transduction pathways. We also identified nonsteroidal anti-inflammatory drug Sulindac and analogs as effective inhibitors of tRXRα activities via a unique binding mechanism. This review discusses the emerging roles of tRXRα and modulators in the regulation of cancer cell survival and death as well as inflammation and our recent understanding of tRXRα regulation by targeting the alternate binding sites on its surface.
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Affiliation(s)
- Xiaokun Zhang
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China Sanford Burnham Prebys Medical Discovery Institute, Cancer Center, La Jolla, CA 92037, USA
| | - Hu Zhou
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
| | - Ying Su
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China Sanford Burnham Prebys Medical Discovery Institute, Cancer Center, La Jolla, CA 92037, USA
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Agostini-Dreyer A, Jetzt AE, Stires H, Cohick WS. Endogenous IGFBP-3 Mediates Intrinsic Apoptosis Through Modulation of Nur77 Phosphorylation and Nuclear Export. Endocrinology 2015; 156:4141-51. [PMID: 26340041 DOI: 10.1210/en.2015-1215] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
In nontransformed bovine mammary epithelial cells, the intrinsic apoptosis inducer anisomycin (ANS) induces IGFBP-3 expression and nuclear localization and knockdown of IGFBP-3 attenuates ANS-induced apoptosis. Others have shown in prostate cancer cells that exogenous IGFBP-3 induces apoptosis by facilitating nuclear export of the orphan nuclear receptor Nur77 and its binding partner, retinoid X receptor-α (RXRα). The goal of the present work was to determine whether endogenous IGFBP-3 plays a role in ANS-induced apoptosis by facilitating nuclear transport of Nur77 and/or RXRα in nontransformed cells. Knockdown of Nur77 with siRNA decreased ANS-induced cleavage of caspase-3 and -7 and their downstream target, PARP, indicating a role for Nur77 in ANS-induced apoptosis. In cells transfected with IGFBP-3, IGFBP-3 associated with RXRα but not Nur77 under basal conditions, however, IGFBP-3 co-precipitated with phosphorylated forms of both proteins in ANS-treated cells. Indirect immunofluorescence and cell fractionation techniques showed that ANS induced phosphorylation and transport of Nur77 from the nucleus to the cytoplasm and these effects were attenuated by knockdown of IGFBP-3. These data suggest that endogenous IGFBP-3 plays a role in intrinsic apoptosis by facilitating phosphorylation and nuclear export of Nur77 to the cytoplasm where it exerts its apoptotic effect. Whether this mechanism involves a physical association between endogenous IGFBP-3 and Nur77 or RXRα remains to be determined.
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Affiliation(s)
- Allyson Agostini-Dreyer
- Graduate Program in Nutritional Sciences (A.A.-D., W.S.C.), Department of Animal Sciences, Rutgers (A.E.J., W.S.C.), and Graduate Program in Endocrinology and Animal Biosciences (H.S., W.S.C.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8520
| | - Amanda E Jetzt
- Graduate Program in Nutritional Sciences (A.A.-D., W.S.C.), Department of Animal Sciences, Rutgers (A.E.J., W.S.C.), and Graduate Program in Endocrinology and Animal Biosciences (H.S., W.S.C.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8520
| | - Hillary Stires
- Graduate Program in Nutritional Sciences (A.A.-D., W.S.C.), Department of Animal Sciences, Rutgers (A.E.J., W.S.C.), and Graduate Program in Endocrinology and Animal Biosciences (H.S., W.S.C.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8520
| | - Wendie S Cohick
- Graduate Program in Nutritional Sciences (A.A.-D., W.S.C.), Department of Animal Sciences, Rutgers (A.E.J., W.S.C.), and Graduate Program in Endocrinology and Animal Biosciences (H.S., W.S.C.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8520
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Zhang XK, Su Y, Chen L, Chen F, Liu J, Zhou H. Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites. Acta Pharmacol Sin 2015; 36:102-12. [PMID: 25434990 DOI: 10.1038/aps.2014.109] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 09/28/2014] [Indexed: 12/31/2022]
Abstract
Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.
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15
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The interplay of NR4A receptors and the oncogene-tumor suppressor networks in cancer. Cell Signal 2014; 27:257-66. [PMID: 25446259 DOI: 10.1016/j.cellsig.2014.11.009] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 10/25/2014] [Accepted: 11/08/2014] [Indexed: 12/11/2022]
Abstract
Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiological and pathological roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro-oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Additionally, NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways.
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Polvani S, Tarocchi M, Tempesti S, Galli A. Nuclear receptors and pathogenesis of pancreatic cancer. World J Gastroenterol 2014; 20:12062-12081. [PMID: 25232244 PMCID: PMC4161795 DOI: 10.3748/wjg.v20.i34.12062] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
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NR4A nuclear receptors are orphans but not lonesome. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2543-2555. [PMID: 24975497 DOI: 10.1016/j.bbamcr.2014.06.010] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/13/2014] [Accepted: 06/17/2014] [Indexed: 01/23/2023]
Abstract
The NR4A subfamily of nuclear receptors consists of three mammalian members: Nur77, Nurr1, and NOR-1. The NR4A receptors are involved in essential physiological processes such as adaptive and innate immune cell differentiation, metabolism and brain function. They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to steroid hormone nuclear receptors such as the estrogen receptor or the glucocorticoid receptor, no ligands have been described for the NR4A receptors. This lack of known ligands might be explained by the structure of the ligand-binding domain of NR4A receptors, which shows an active conformation and a ligand-binding pocket that is filled with bulky amino acid side-chains. Other mechanisms, such as transcriptional control, post-translational modifications and protein-protein interactions therefore seem to be more important in regulating the activity of the NR4A receptors. For Nur77, over 80 interacting proteins (the interactome) have been identified so far, and roughly half of these interactions has been studied in more detail. Although the NR4As show some overlap in interacting proteins, less information is available on the interactome of Nurr1 and NOR-1. Therefore, the present review will describe the current knowledge on the interactomes of all three NR4A nuclear receptors with emphasis on Nur77.
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Wu Y, Ye Y, Shi Y, Li P, Xu J, Chen K, Xu E, Yang J. Association between vitamin A, retinol intake and blood retinol level and gastric cancer risk: A meta-analysis. Clin Nutr 2014; 34:620-6. [PMID: 25008141 DOI: 10.1016/j.clnu.2014.06.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 05/15/2014] [Accepted: 06/17/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND & AIMS The association between dietary vitamin A, retinol intake and blood retinol level and gastric cancer risk has been investigated by many studies. However, the results of these studies were controversial. The aim of our study was to systematically assess this issue. METHODS PUBMED and EMBASE were searched, supplemented with manual-screening for relevant publications. Meta-analyses were performed to evaluate the association between vitamin A, retinol dietary intake or blood retinol level and gastric cancer risk. RESULTS Thirty-one studies were included in this meta-analysis. Comparing the highest with the lowest categories, vitamin A intake significantly reduced gastric cancer risk (pooled RR = 0.66, 95% CI: 0.52-0.84), whereas a marginally inverse association was found between retinol intake (pooled RR = 0.94, 95% CI: 0.87-1.03) or blood retinol level (pooled RR = 0.87, 95% CI: 0.73-1.05) and gastric cancer risk. Interestingly, the results of subgroup analysis indicated that high vitamin A intake and blood retinol level were associated with reduced gastric cancer risk in Western countries, while a marginally inverse association was found between retinol and gastric cancer risk in Western countries. CONCLUSIONS Vitamin A intake was inversely associated with gastric cancer risk, while no significant association was found with retinol intake or blood retinol level.
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Affiliation(s)
- Yihua Wu
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou 310058, China
| | - Yao Ye
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou 310058, China
| | - Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Peiwei Li
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou 310058, China
| | - Jinming Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou 310058, China
| | - Kun Chen
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou 310058, China
| | - Enping Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Jun Yang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China; Department of Medicine, Hangzhou Normal University, 16, Xuelin Str., Xiasha High Education Zone, Hangzhou, Zhejiang 310036, China.
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Niu G, Lu L, Gan J, Zhang D, Liu J, Huang G. Dual roles of orphan nuclear receptor TR3/Nur77/NGFI-B in mediating cell survival and apoptosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 313:219-58. [PMID: 25376494 DOI: 10.1016/b978-0-12-800177-6.00007-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
As a transcriptional factor, Nur77 has sparked interests across different research fields in recent years. A number of studies have demonstrated the functional complexity of Nur77 in mediating survival/apoptosis in a variety of cells, including tumor cells. Conflicting observations also exist in clinical reports, in that TR3 behaves like an oncogene in tumors of the GI tract, lung, and breast, that is negatively associated with tumor stage and patient prognosis; while functions as a tumor suppressor gene in malignancies of the hematological and lymphatic system, skin, and ovary whose malfunction results in carcinogenesis. This chapter summarizes the apparent opposing effects of Nur77 on cells and explicates the mechanisms that determine the functional preference of Nur77. We conclude that in addition to cell type and agent context, other factors such as cellular localization, signaling pathway, and posttranslational modification also determine the final effects of Nur77 on cells.
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Affiliation(s)
- Gengming Niu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lei Lu
- Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Jun Gan
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Di Zhang
- Main Library, Shanghai Jiao Tong University, Shanghai, China
| | - Jingzheng Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guangjian Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Hu KW, Chen FH, Ge JF, Cao LY, Li H. Retinoid receptors in gastric cancer: expression and influence on prognosis. Asian Pac J Cancer Prev 2013; 13:1809-17. [PMID: 22901127 DOI: 10.7314/apjcp.2012.13.5.1809] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, α, β and γ. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. PATIENTS AND METHODS We retrospectively analyzed the expression of the subtypes RARα, RARβ, RARγ, RXRα, RXRβ, RXRγ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using real- time PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). RESULTS RARα, RARβ, RARγ and RXRγ positively correlated with each other (p<0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p<0.01), with lower RARβ, RARγ and RXRα expression significantly related to advanced stages (p<=0.01). Tumors with poor histopathologic grade had lower levels of RARα and RARβ in different histological types of gastric carcinoma (p<0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p<0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p=0.007, HR=0.41, 95.0% CI 0.21-0.80). CONCLUSIONS Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.
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Affiliation(s)
- Kong-Wang Hu
- Department of General Surgery, the First Hospital of Anhui Medical University, School of Pharmacology, Anhui Medical University, Hefei, China
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Boldingh Debernard KA, Mathisen GH, Paulsen RE. Differences in NGFI-B, Nurr1, and NOR-1 expression and nucleocytoplasmic translocation in glutamate-treated neurons. Neurochem Int 2012; 61:79-88. [PMID: 22525717 DOI: 10.1016/j.neuint.2012.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 03/21/2012] [Accepted: 04/05/2012] [Indexed: 11/30/2022]
Abstract
NGFI-B (NR4A1, Nur77 or TR3) together with Nurr1 (NR4A2) and NOR-1 (NR4A3) constitute the NR4A subgroup of orphan nuclear receptors. They play critical roles in proliferation, differentiation, survival and apoptosis in different cell types, including neurons, immature T-cells, and different cancer cells. As ligand-independent and constitutively active receptors, the diverse biological activities of NGFI-B, Nurr1 and NOR-1 depend on their levels of expression, post-translational modifications and subcellular localization. Nuclear localization of the NR4A proteins leads to transcriptional activity, whereas NGFI-B and recently also NOR-1 have been shown to induce apoptosis by a more direct mechanism when localized at mitochondria. In the present study we investigated mRNA expression and subcellular translocation of the NR4A proteins during glutamate excitotoxicity in rat cerebellar granule neurons. NGFI-B and Nurr1 mRNA, but not NOR-1 mRNA, were induced by treatments associated with calcium influx, although their regulation seemed to be different. NR4A(gfp) fusion proteins showed a predominant nuclear localization in untreated cells. After glutamate treatment NGFI-B(gfp) translocated to cytosol and mitochondria within a few hours, whereas Nurr1(gfp) translocation was delayed, and NOR-1(gfp) mainly stayed in the nucleus. Subcellular targeting of NGFI-B seems to be tightly regulated, as a single mutation of threonine 142 altered NGFI-B(gfp) localization. Differences in expression and subcellular translocation of NGFI-B, Nurr1, and NOR-1 may reflect different functions in neurons in glutamate excitotoxicity.
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Johnston DM, Sedkov Y, Petruk S, Riley KM, Fujioka M, Jaynes JB, Mazo A. Ecdysone- and NO-mediated gene regulation by competing EcR/Usp and E75A nuclear receptors during Drosophila development. Mol Cell 2011; 44:51-61. [PMID: 21981918 DOI: 10.1016/j.molcel.2011.07.033] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Revised: 05/26/2011] [Accepted: 07/07/2011] [Indexed: 11/19/2022]
Abstract
The Drosophila ecdysone receptor (EcR/Usp) is thought to activate or repress gene transcription depending on the presence or absence, respectively, of the hormone ecdysone. Unexpectedly, we found an alternative mechanism at work in salivary glands during the ecdysone-dependent transition from larvae to pupae. In the absense of ecdysone, both ecdysone receptor subunits localize to the cytoplasm, and the heme-binding nuclear receptor E75A replaces EcR/Usp at common target sequences in several genes. During the larval-pupal transition, a switch from gene activation by EcR/Usp to gene repression by E75A is triggered by a decrease in ecdysone concentration and by direct repression of the EcR gene by E75A. Additional control is provided by developmentally timed modulation of E75A activity by NO, which inhibits recruitment of the corepressor SMRTER. These results suggest a mechanism for sequential modulation of gene expression during development by competing nuclear receptors and their effector molecules, ecdysone and NO.
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Affiliation(s)
- Danika M Johnston
- Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Yao LM, He JP, Chen HZ, Wang Y, Wang WJ, Wu R, Yu CD, Wu Q. Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis. Carcinogenesis 2011; 33:301-11. [DOI: 10.1093/carcin/bgr287] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Dawson MI, Xia Z. The retinoid X receptors and their ligands. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:21-56. [PMID: 22020178 DOI: 10.1016/j.bbalip.2011.09.014] [Citation(s) in RCA: 269] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Revised: 08/23/2011] [Accepted: 09/23/2011] [Indexed: 12/12/2022]
Abstract
This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1-3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand-bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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Affiliation(s)
- Marcia I Dawson
- Cancer Center, Sanford-Burn Medical Research Institute, 10901 North Torrey Pines Rd., La Jolla, CA 93207, USA.
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Delayed translocation of NGFI–B/RXR in glutamate stimulated neurons allows late protection by 9-cis retinoic acid. Biochem Biophys Res Commun 2011; 414:90-5. [DOI: 10.1016/j.bbrc.2011.09.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 09/03/2011] [Indexed: 01/15/2023]
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Gammal R, Baker K, Heilman D. Heterokaryon technique for analysis of cell type-specific localization. J Vis Exp 2011:2488. [PMID: 21445034 PMCID: PMC3197295 DOI: 10.3791/2488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A significant number of proteins are regulated by subcellular trafficking or nucleocytolasmic shuttling. These proteins display a diverse array of cellular functions including nuclear import/export of RNA and protein, transcriptional regulation, and apoptosis. Interestingly, major cellular reorganizations including cell division, differentiation and transformation, often involve such activities. The detailed study of these proteins and their respective regulatory mechanisms can be challenging as the stimulation for these localization changes can be elusive, and the movements themselves can be quite dynamic and difficult to track. Studies involving cellular oncogenesis, for example, continue to benefit from understanding pathways and protein activities that differ between normal primary cells and transformed cells. As many proteins show altered localization during transformation or as a result of transformation, methods to efficiently characterize these proteins and the pathways in which they participate stand to improve the understanding of oncogenesis and open new areas for drug targeting. Here we present a method for the analysis of protein trafficking and shuttling activity between primary and transformed mammalian cells. This method combines the generation of heterokaryon fusions with fluorescence microscopy to provide a flexible protocol that can be used to detect steady-state or dynamic protein localizations. As shown in Figure 1, two separate cell types are transiently transfected with plasmid constructs bearing a fluoroprotein gene attached to the gene of interest. After expression, the cells are fused using polyethylene glycol, and protein localizations may then be imaged using a variety of methods. The protocol presented here is a fundamental approach to which specialized techniques may be added.
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Affiliation(s)
- Roseann Gammal
- Department of Chemistry and Biochemistry, Worcester Polytechnic Institute
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Lee SO, Li X, Khan S, Safe S. Targeting NR4A1 (TR3) in cancer cells and tumors. Expert Opin Ther Targets 2011; 15:195-206. [PMID: 21204731 DOI: 10.1517/14728222.2011.547481] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Nuclear receptor 4A1(NR4A1) (testicular receptor 3 (TR3), nuclear hormone receptor (Nur)77) is a member of the nuclear receptor superfamily of transcription factors and is highly expressed in multiple tumor types. RNA interference studies indicate that NR4A1 exhibits growth-promoting, angiogenic and prosurvival activity in most cancers. AREAS COVERED Studies on several apoptosis-inducing agents that activate nuclear export of NR4A1, which subsequently forms a mitochondrial NR4A1-bcl-2 complex that induces the intrinsic pathway for apoptosis are discussed. Cytosporone B and related compounds that induce NR4A1-dependent apoptosis in cancer cells through both modulation of nuclear NR4A1 and nuclear export are discussed. A relatively new class of diindolylmethane analogs (C-DIMs) including 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH(3)) (NR4A1 activator) and 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) (NR4A1 deactivator) are discussed in more detail. These anticancer drugs (C-DIMs) act strictly through nuclear NR4A1 and induce apoptosis in cancer cells and tumors. EXPERT OPINION It is clear that NR4A1 plays an important pro-oncogenic role in cancer cells and tumors, and there is increasing evidence that this receptor can be targeted by anticancer drugs that induce cell death via NR4A1-dependent and -independent pathways. Since many of these compounds exhibit relatively low toxicity, they represent an important class of mechanism-based anticancer drugs with excellent potential for clinical applications.
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Affiliation(s)
- Syng-Ook Lee
- Institute of Bioscience and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA
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Lindenboim L, Borner C, Stein R. Nuclear proteins acting on mitochondria. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2010; 1813:584-96. [PMID: 21130123 DOI: 10.1016/j.bbamcr.2010.11.016] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 11/08/2010] [Accepted: 11/23/2010] [Indexed: 12/23/2022]
Abstract
An important mechanism in apoptotic regulation is changes in the subcellular distribution of pro- and anti-apoptotic proteins. Among the proteins that change in their localization and may promote apoptosis are nuclear proteins. Several of these nuclear proteins such as p53, Nur77, histone H1.2, and nucleophosmin were reported to accumulate in the cytosol and/or mitochondria and to promote the mitochondrial apoptotic pathway in response to apoptotic stressors. In this review, we will discuss the functions of these and other nuclear proteins in promoting the mitochondrial apoptotic pathway, the mechanisms that regulate their accumulation in the cytosol and/or mitochondria and the potential role of Bax and Bak in this process. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
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Affiliation(s)
- Liora Lindenboim
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Ramat Aviv, Israel
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Lefebvre P, Benomar Y, Staels B. Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab 2010; 21:676-83. [PMID: 20674387 DOI: 10.1016/j.tem.2010.06.009] [Citation(s) in RCA: 220] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Revised: 06/25/2010] [Accepted: 06/29/2010] [Indexed: 01/19/2023]
Abstract
Retinoid X receptors (RXRs) have been implicated in a diversity of cellular processes ranging from cellular proliferation to lipid metabolism. These pleiotropic effects stem not only from the ability of RXRs to dimerize with diverse nuclear receptors, which exert transcriptional control on specific aspects of cell biology, but also because binding of RXR ligands to heterodimers can stimulate transcriptional activation by RXR partner receptors. This signaling network is rendered more complex by the existence of different RXR isotypes (RXRα, RXRβ, RXRγ) with distinct properties that thereby modulate the transcriptional activity of RXR-containing heterodimers. This review discusses the emerging roles of RXR isotypes in the RXR signaling network and possible implications for our understanding of nuclear receptor biology and pharmacology.
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Liu JJ, Zeng HN, Zhang LR, Zhan YY, Chen Y, Wang Y, Wang J, Xiang SH, Liu WJ, Wang WJ, Chen HZ, Shen YM, Su WJ, Huang PQ, Zhang HK, Wu Q. A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res 2010; 70:3628-37. [PMID: 20388790 DOI: 10.1158/0008-5472.can-09-3160] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents.
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Affiliation(s)
- Jing-jing Liu
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, PR China
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Carter CJ, Farrar N, Carlone RL, Spencer GE. Developmental expression of a molluscan RXR and evidence for its novel, nongenomic role in growth cone guidance. Dev Biol 2010; 343:124-37. [PMID: 20381485 DOI: 10.1016/j.ydbio.2010.03.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 03/10/2010] [Accepted: 03/25/2010] [Indexed: 02/06/2023]
Abstract
It is well known that the vitamin A metabolite, retinoic acid, plays an important role in vertebrate development and regeneration. We have previously shown that the effects of RA in mediating neurite outgrowth, are conserved between vertebrates and invertebrates (Dmetrichuk et al., 2005, 2006) and that RA can induce growth cone turning in regenerating molluscan neurons (Farrar et al., 2009). In this study, we have cloned a retinoid receptor from the mollusc Lymnaea stagnalis (LymRXR) that shares about 80% amino acid identity with the vertebrate RXRalpha. We demonstrate using Western blot analysis that the LymRXR is present in the developing Lymnaea embryo and that treatment of embryos with the putative RXR ligand, 9-cis RA, or a RXR pan-agonist, PA024, significantly disrupts embryogenesis. We also demonstrate cytoplasmic localization of LymRXR in adult central neurons, with a strong localization in the neuritic (or axonal) domains. Using regenerating cultured motor neurons, we show that LymRXR is also present in the growth cones and that application of a RXR pan-agonist produces growth cone turning in isolated neurites (in the absence of the cell body and nucleus). These data support a role for RXR in growth cone guidance and are the first studies to suggest a nongenomic action for RXR in the nervous system.
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Affiliation(s)
- Christopher J Carter
- Dept. Biological Sciences, Brock University, 500 Glenridge Ave. St. Catharines, Ontario, Canada L2S 3A1
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Yang H, Bushue N, Bu P, Wan YJY. Induction and intracellular localization of Nur77 dictate fenretinide-induced apoptosis of human liver cancer cells. Biochem Pharmacol 2009; 79:948-54. [PMID: 19912993 DOI: 10.1016/j.bcp.2009.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2009] [Revised: 11/02/2009] [Accepted: 11/02/2009] [Indexed: 01/14/2023]
Abstract
Fenretinide, a synthetic retinoid, is known to induce apoptosis in various cancer cells. However, the mechanism by which fenretinide induces apoptosis remains unclear. The current study examines the mechanisms of fenretinide-induced apoptosis in human hepatoma cells. The induction of Nur77 and the cytoplasmic distribution of Nur77 induced by fenretinide were positively correlated with the apoptotic effect of fenretinide in HCC cells. The sensitivity of Huh-7 cells was related to Nur77 translocation and targeting mitochondria, whereas the mechanism of resistance for HepG2 cells seemed due to Nur77 accumulating in the nucleus. The intracellular location of Nur77 was also associated with the differential capability of fenretinide-induced ROS generation in these two cell lines. In addition, the knockdown of Nur77 expression by siRNA greatly reduced fenretinide-induced apoptosis and cleaved caspase 3 in Huh-7 cells. Therefore, our findings demonstrate that fenretinide-induced apoptosis of HCC cells is Nur77 dependent and that the intracellular localization of Nur77 dictates the sensitivity of the HCC cells to fenretinide-induced apoptosis.
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Affiliation(s)
- Hui Yang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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Yung TM, Narita T, Komori T, Yamaguchi Y, Handa H. Cellular dynamics of the negative transcription elongation factor NELF. Exp Cell Res 2009; 315:1693-705. [DOI: 10.1016/j.yexcr.2009.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Revised: 02/12/2009] [Accepted: 02/12/2009] [Indexed: 10/21/2022]
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9-cis retinoic acid induces retinoid X receptor localized to the mitochondria for mediation of mitochondrial transcription. Biochem Biophys Res Commun 2008; 377:351-354. [DOI: 10.1016/j.bbrc.2008.09.122] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Accepted: 09/26/2008] [Indexed: 11/19/2022]
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Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol 2008; 4:548-56. [PMID: 18690216 DOI: 10.1038/nchembio.106] [Citation(s) in RCA: 269] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Accepted: 07/14/2008] [Indexed: 01/25/2023]
Abstract
Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.
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Chen HZ, Zhao BX, Zhao WX, Li L, Zhang B, Wu Q. Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria. Carcinogenesis 2008; 29:2078-88. [PMID: 18713840 DOI: 10.1093/carcin/bgn197] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) phosphorylates and regulates the function of many cellular proteins involved in processes such as metabolism, apoptosis and proliferation. However, the precise mechanisms by which Akt promotes cell survival and inhibits apoptosis have been characterized in part only. TR3, an orphan receptor, functions as a transcription factor that can both positively or negatively regulate gene expression. We have reported previously that the translocation of TR3 from the nucleus to the mitochondria can elicit a proapoptotic effect in gastric cancer cells. In our present study, we demonstrate that Akt phosphorylates cytoplasmic TR3 through its physical interaction with the N-terminus of TR3. When coexpressed with Akt, TR3 mitochondrial targeting was blocked and this protein adopted a diffuse expression pattern in the cytoplasm. Moreover, Akt displayed an ability to disrupt the interaction of TR3 with Bcl-2, which is thought to be a critical requirement for mitochondrial TR3 to elicit apoptosis. Consistently, insulin was also found to induce the phosphorylation of TR3 and abolish 12-O-tetradecanoylphorbol-13-acetate-induced mitochondrial localization, which was dependent upon the activation of the phophatidylinositol-3-OH-kinase-Akt signaling pathway. Taken together, our current data demonstrate a unique role for Akt in inhibiting TR3 functions that are not related to transcriptional activity but that correlate with the regulation of its mitochondrial association. This may represent a novel signal pathway by which Akt exerts its antiapoptotic effects in gastric cancer cells, i.e. by regulating the phosphorylation and redistribution of orphan receptors.
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Affiliation(s)
- Hang-Zi Chen
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China
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Dillard AC, Lane MA. Retinol Increases beta-catenin-RXRalpha binding leading to the increased proteasomal degradation of beta-catenin and RXRalpha. Nutr Cancer 2008; 60:97-108. [PMID: 18444141 DOI: 10.1080/01635580701586754] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Retinol utilizes a retinoid X receptor (RXR)-mediated degradation pathway to decrease beta-catenin protein in all-trans retinoic acid (ATRA)-resistant human colon cancer cells. In this study, we examined interactions between RXRalpha and beta-catenin in ATRA-resistant human colon cancer cells treated with retinol. Retinol treatment triggers relocation of beta-catenin and RXRalpha proteins. Cells treated with retinol for 8 and 24 h displayed increased cytosolic but decreased nuclear beta-catenin and RXRalpha. Retinol treatment increased beta-catenin and RXRalpha protein interaction. Previously, we showed that 24 h of retinol treatment increased RXRalpha protein. Here we show this increase in RXRalpha levels is due to increased RXRalpha messenger RNA. Treatment with 48 h with retinol decreased RXRalpha protein levels. Last, by transfecting HCT-116 cells with a RXRalpha construct lacking the activation function-1 and DNA binding domains, we show RXRalpha and beta-catenin binding is required for proteosomal degradation of beta-catenin. These results suggest retinol induces RXRalpha and beta-catenin binding and transport to the cytosol where they are proteasomally degraded.
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Affiliation(s)
- Alice C Dillard
- Department of Human Ecology, Division of Nutritional Sciences, The University of Texas at Austin, Austin, TX 78712, USA
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Sibayama-Imazu T, Fujisawa Y, Masuda Y, Aiuchi T, Nakajo S, Itabe H, Nakaya K. Induction of apoptosis in PA-1 ovarian cancer cells by vitamin K2 is associated with an increase in the level of TR3/Nur77 and its accumulation in mitochondria and nuclei. J Cancer Res Clin Oncol 2008; 134:803-12. [PMID: 18202854 DOI: 10.1007/s00432-007-0349-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2007] [Accepted: 12/03/2007] [Indexed: 12/11/2022]
Abstract
PURPOSE We examined the growth-inhibitory and apoptosis-inducing effects of vitamin K(2) (VK(2); menaquinone-4) on various lines of human ovarian cancer cells to study the mechanism of induction of apoptosis by VK(2). METHODS Cell proliferation was determined by XTT method, and apoptotic cells were detected by Hoechst staining. TR3, also known as Nur77 and NGFI-B, was detected by immunoblotting and immunofluorescence analysis. Role of TR3 on induction of apoptosis was examined by a siRNA experiment. RESULTS AND CONCLUSIONS We found that PA-1 cells were the most sensitive to VK(2) (IC(50) = 5.0 +/- 0.7 microM), while SK-OV-3 cells were resistant to VK(2). Immunoblotting and immunofluorescence analyses indicated that levels of TR3 were elevated in cell lysates 48 h after the start of treatment with 30 microM VK(2). In the VK(2)-treated cells, TR3 accumulated at significant levels in mitochondria, as well as in the nuclei of PA-1 cells. No similar changes were observed in SK-OV-3 cells under the same conditions. Treatment of PA-1 cells with small interfering RNA (siRNA) directed against TR3, and with cycloheximide or SP600125 (an inhibitor of c-jun N-terminal kinase; JNK), separately, inhibited the VK(2)-induced synthesis of TR3 and apoptosis. From these results, we can conclude that an increase in the synthesis of TR3 and the accumulation of TR3 in mitochondria and in nuclei might be involved in the induction of apoptosis by VK(2) and that the synthesis of TR3 might be regulated through a JNK signaling pathway.
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Affiliation(s)
- Toshiko Sibayama-Imazu
- Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
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Zhao WX, Tian M, Zhao BX, Li GD, Liu B, Zhan YY, Chen HZ, Wu Q. Orphan receptor TR3 attenuates the p300-induced acetylation of retinoid X receptor-alpha. Mol Endocrinol 2007; 21:2877-89. [PMID: 17761950 DOI: 10.1210/me.2007-0107] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Acetylation modification regulates the functions of histone and nonhistone proteins, including transcriptional activity, protein interaction, and subcellular localization. Although many nuclear receptors have been shown to be modified by acetylation, whether retinoid X receptors (RXRs) are acetylated and how the acetylation is regulated remains unknown. Here, we provide the first evidence of RXRalpha acetylation by p300 on lysine 145. Acetylation of RXRalpha by p300 facilitated its DNA binding and subsequently increased its transcriptional activity. Furthermore, we discovered that TR3, an orphan receptor, exerted a negative regulation on p300-induced RXRalpha acetylation. TR3 significantly reduced the p300-induced RXRalpha acetylation and transcriptional activity, and such inhibition required the interaction of TR3 with RXRalpha. Binding of TR3 to RXRalpha resulted in the sequestration of RXRalpha from p300. 9-cis retinoic acid, a ligand for RXRalpha, enhanced the association of RXRalpha with TR3, rather than acetylation of RXRalpha by p300. Biological function analysis revealed that the mitogenic activity of RXRalpha stimulated by p300 was acetylation dependent and could be repressed by TR3. Upon the treatment of 9-cis retinoic acid, RXRalpha was translocated with TR3 from the nucleus to the mitochondria, and apoptosis was induced. Taken together, our data demonstrate the distinct regulatory mechanisms of p300 and TR3 on RXRalpha acetylation and reveal a previously unrecognized role for orphan receptor in the transcriptional control of retinoid receptors.
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Affiliation(s)
- Wen-Xiu Zhao
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China
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Chakravarti N, Lotan R, Diwan AH, Warneke CL, Johnson MM, Prieto VG. Decreased Expression of Retinoid Receptors in Melanoma: Entailment in Tumorigenesis and Prognosis. Clin Cancer Res 2007; 13:4817-24. [PMID: 17699860 DOI: 10.1158/1078-0432.ccr-06-3026] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate the various modulatory effects of retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (alpha, beta, gamma) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients. EXPERIMENTAL DESIGN Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (alpha, beta, gamma). RESULTS A significant decrease of RARbeta protein (P < 0.0001), nuclear expression of RARgamma (P < 0.0001), and RXRalpha (P < 0.0001) was found in primary and metastatic melanomas as compared with nevi. Loss of nuclear immunoreactivity for RARgamma (P = 0.048) and RXRalpha (P = 0.001) was observed in the lesions showing vertical growth pattern. In addition, in patients with concomitant loss of cytoplasmic staining for RARalpha and RXRalpha, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower. CONCLUSIONS Aberrant expression of retinoid receptors seems to be a frequent event in melanoma and suggests an impairment of the retinoid pathway in this cancer. Our data indicate the loss of retinoid receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of retinoid receptors in melanoma.
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Affiliation(s)
- Nitin Chakravarti
- Department of Head and Neck/Thoracic Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Fu J, Ding Y, Huang D, Li H, Chen X. The retinoid X receptor-selective ligand, LGD1069, inhibits tumor-induced angiogenesis via suppression of VEGF in human non-small cell lung cancer. Cancer Lett 2007; 248:153-63. [PMID: 17027148 DOI: 10.1016/j.canlet.2006.06.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2006] [Revised: 06/04/2006] [Accepted: 06/30/2006] [Indexed: 10/24/2022]
Abstract
The present study determined the influence of a retinoid X receptor agonist LGD1069 on angiogenesis in non-small cell lung cancer. In A549 xenograft models, treatment with LGD1069 inhibited the growth and CD31 expression compared with control. In vivo angiogenesis assay utilizing hollow fiber, LGD1069 reduced density of capillary network induced by tumor cells. To determine the basis of these observations, we examined the expression of VEGF and activation of JNK and ERK in A549 cells exposed to LGD1069. Our data showed that LGD1069 decrease the VEGF expression of tumor cells in a dose-dependent manner. Furthermore, it was demonstrated that the decreasing expression of VEGF was consist with inhibition of JNK and ERK activation induced by LGD1069. Collectively, our results suggest a role of LGD1069 in treatment for non-small cell lung cancer by inhibition of tumor-induced angiogenesis.
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MESH Headings
- Animals
- Anticarcinogenic Agents/pharmacology
- Anticarcinogenic Agents/therapeutic use
- Bexarotene
- Blotting, Western
- Carcinoma, Non-Small-Cell Lung/blood supply
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/prevention & control
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Enzyme Activation/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- HT29 Cells
- Humans
- Immunohistochemistry
- JNK Mitogen-Activated Protein Kinases/metabolism
- Lung Neoplasms/blood supply
- Lung Neoplasms/metabolism
- Lung Neoplasms/prevention & control
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/metabolism
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/prevention & control
- Platelet Endothelial Cell Adhesion Molecule-1/analysis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Retinoid X Receptors/agonists
- Retinoid X Receptors/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Tetrahydronaphthalenes/pharmacology
- Tetrahydronaphthalenes/therapeutic use
- Vascular Endothelial Growth Factor A/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Jianjiang Fu
- Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China
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Asin-Cayuela J, Gustafsson CM. Mitochondrial transcription and its regulation in mammalian cells. Trends Biochem Sci 2007; 32:111-7. [PMID: 17291767 DOI: 10.1016/j.tibs.2007.01.003] [Citation(s) in RCA: 160] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2006] [Revised: 01/25/2007] [Accepted: 01/30/2007] [Indexed: 02/08/2023]
Abstract
Human mitochondria contain multiple copies of a small double-stranded DNA genome that encode 13 components of the electron-transport chain and RNA components that are needed for mitochondrial translation. The mitochondrial genome is transcribed by a specialized machinery that includes a monomeric RNA polymerase, the mitochondrial transcription factor A and one of the two mitochondrial transcription factor B paralogues, TFB1M or TFB2M. Today, the components of the basal transcription machinery in mammalian mitochondria are known and their mechanisms of action are gradually being established. In addition, regulatory factors govern transcription levels both at the stage of initiation and termination, but the detailed biochemical understanding of these processes is largely missing.
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Affiliation(s)
- Jordi Asin-Cayuela
- Division of Metabolic Diseases, Karolinska Institutet, Novum, SE-141 86, Stockholm, Sweden
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Abstract
The ultimate growth of a tumour depends on not only the rate of tumour cell proliferation, but also the rate of tumour cell death (apoptosis). Nur77 (also known as TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, controls both survival and death of cancer cells. A wealth of recent experimental data demonstrates that the Nur77 activities are regulated through its subcellular localisation. In the nucleus, Nur77 functions as an oncogenic survival factor, promoting cancer cell growth. In contrast, it is a potent killer when migrating to mitochondria, where it binds to Bcl-2 and converts its survival phenotype, triggering cytochrome c release and apoptosis. Agents, such as 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437), which induce Nur77 migration from the nucleus to mitochondria, effectively induce apoptosis of cancer cells. Moreover, Nur77 translocation is highly controlled by retinoid X receptor (RXR), suggesting a role of RXR ligands in regulating the process. Thus, translocation of Nur77 from the nucleus to mitochondria represents a new paradigm in cancer cell apoptosis, and targeting the Nur77 translocation by AHPN/CD437 or RXR ligands promises to effectively restrict cancer cell growth by simultaneously promoting cancer cell death and suppressing cancer cell proliferation.
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Affiliation(s)
- Xiao-kun Zhang
- Burnham Institute for Medical Research, Cancer Center, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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Yan G, Luo W, Lu Z, Luo X, Li L, Liu S, Liu Y, Tang M, Dong Z, Cao Y. Epstein–Barr virus latent membrane protein 1 mediates phosphorylation and nuclear translocation of annexin A2 by activating PKC pathway. Cell Signal 2007; 19:341-8. [PMID: 16989986 DOI: 10.1016/j.cellsig.2006.07.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Revised: 06/28/2006] [Accepted: 07/19/2006] [Indexed: 01/14/2023]
Abstract
We have previously combined phosphorylation enrichment with proteomics technology to elucidate the novel phosphoproteins in the signaling pathways triggered by Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) and shown that LMP1 can increase the phosphorylation level of annexin A2. Here, we further showed that LMP1 increased the serine, but not tyrosine, phosphorylation of annexin A2 by activating a novel signaling pathway, the protein kinase C (PKC) signaling pathway. However, LMP1 did not affect the level of annexin A2 expression. In addition, we found that LMP1 induced the nuclear entry of annexin A2 in an energy- and temperature-dependent manner, suggesting that the nuclear entry of annexin A2 is an active process. Treatment of LMP1-expressing cells with the PKC inhibitor myr-psiPKC resulted in annexin A2 being present almost exclusively at cell surface, instead of within the nucleus, suggesting that the nuclear entry of annexin A2 was associated with serine phosphorylation mediated by PKC.
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Affiliation(s)
- Guangrong Yan
- Cancer Research Institute, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China
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45
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Zhao BX, Chen HZ, Lei NZ, Li GD, Zhao WX, Zhan YY, Liu B, Lin SC, Wu Q. p53 mediates the negative regulation of MDM2 by orphan receptor TR3. EMBO J 2006; 25:5703-15. [PMID: 17139261 PMCID: PMC1698882 DOI: 10.1038/sj.emboj.7601435] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Accepted: 10/19/2006] [Indexed: 02/07/2023] Open
Abstract
MDM2 is an oncoprotein whose transforming potential is activated by overexpression. The expression level of MDM2 is negatively regulated by orphan receptor TR3 that mainly acts as a transcriptional factor to regulate gene expression. However, the underlying mechanism is largely unclear. Here, we present the first evidence that inhibition of TR3 on MDM2 is mediated by p53. We found that TR3 directly interacts with p53 but not MDM2, and such interaction is critical for TR3 to inhibit MDM2 expression. TR3 downregulates p53 transcriptional activity by blocking its acetylation, leading to a decrease on the transcription level of MDM2. Furthermore, TR3 binding to p53 obstructs its ubiquitination and degradation induced by MDM2, resulting in the MDM2 ubiquitination and degradation. In addition, TR3 could enhance p53-mediated apoptosis induced by UV irradiation. Taken together, our findings demonstrate that p53 mediates the suppression of TR3 on MDM2 at both transcriptional and post-transcriptional level and suggest TR3 as a potential target to develop new anticancer agents that restrict MDM2-induced tumor progression.
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Affiliation(s)
- Bi-xing Zhao
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Hang-zi Chen
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Na-zi Lei
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Gui-deng Li
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Wen-xiu Zhao
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yan-yan Zhan
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Bo Liu
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Sheng-cai Lin
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Qiao Wu
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China. Tel.: +86 592 2187959; Fax: +86 592 2086630; E-mail:
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Moll UM, Marchenko N, Zhang XK. p53 and Nur77/TR3 - transcription factors that directly target mitochondria for cell death induction. Oncogene 2006; 25:4725-43. [PMID: 16892086 DOI: 10.1038/sj.onc.1209601] [Citation(s) in RCA: 191] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Conversely, p53 function is altered or attenuated in one way or another in the majority of human cancers. Besides its well-understood action as a transcriptional regulator of multiple apoptotic genes, p53 also exerts a direct pro-apoptotic role at the mitochondria by engaging in protein-protein interactions with anti- and pro-apoptotic Bcl2 family members, thereby executing the shortest known circuitry of p53 death signaling. Nur77, also known as TR3 or NGFI-B, is a unique transcription factor belonging to the orphan nuclear receptor superfamily. Even more extreme than p53, Nur77 can exert opposing biological activities of survival and death. Its activities are regulated by subcellular distribution, expression levels, protein modification and heterodimerization with retinoid X receptor. In cancer cells, Nur77 functions in the nucleus as an oncogenic survival factor, but becomes a potent killer when certain death stimuli induce its migration to mitochondria, where it binds to Bcl2 and conformationally converts it to a killer that triggers cytochrome c release and apoptosis. This review focuses on their unexpected transcription-independent pro-death programs at mitochondria and highlights the remarkable mechanistic similarities between them. Moreover, an accumulating body of evidence provides ample rationale to further investigate how these mitochondrial p53 and Nur77 pathways could become exploitable targets for new cancer therapeutics.
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Affiliation(s)
- U M Moll
- Department of Pathology Stony Brook University, Stony Brook, New York 11794-8691, USA.
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Luo XM, Ross AC. Retinoic acid exerts dual regulatory actions on the expression and nuclear localization of interferon regulatory factor-1. Exp Biol Med (Maywood) 2006; 231:619-31. [PMID: 16636311 PMCID: PMC3843134 DOI: 10.1177/153537020623100517] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Interferon regulatory factor-1 (IRF-1), a transcription factor and tumor suppressor involved in cell growth regulation and immune responses, has been shown to be induced by all-trans retinoic acid (ATRA). However, the factors controlling the cellular location and activity of IRF-1 are not well understood. In this study, we examined the expression of IRF-1 and its nuclear localization, DNA-binding activity, and target gene expression in human mammary epithelial MCF10A cells, a model of breast epithelial cell differentiation and carcinogenesis. Following initial treatment with ATRA, IRF-1 mRNA and protein were induced within 2 hrs, reached a peak (>30-fold induction) at 8 hrs, and declined afterwards. IRF-1 protein was predominantly cytoplasmic during this treatment. Although a second dose of ATRA or Am580 (a related retinoid selective for retinoic acid receptor-alpha [RARalpha]), given 16 hrs after the first dose, restimulated IRF-1 mRNA and protein levels to a similar level to that obtained by the first dose, IRF-1 was predominantly concentrated in the nucleus after restimulation. ATRA and Am580 also increased nuclear RARalpha, whereas retinoid X receptor-alpha (RXRalpha)--a dimerization partner for RARalpha, was localized to the nucleus upon second exposure to ATRA. However, ATRA and Am580 did not regulate the expression or activation of signal transducer and activator of transcription-1 (STAT-1), a transcription factor capable of inducing the expression of IRF-1, indicating an STAT-1-independent mechanism of regulation by ATRA and Am580. The increase in nuclear IRF-1 after retinoid restimulation was accompanied by enhanced binding to an IRF-E DNA response element, and elevated expression of an IRF-1 target gene, 2',5'-oligoadenylate synthetase-2. The dual effect of retinoids in increasing IRF-1 mRNA and protein and in augmenting the nuclear localization of IRF-1 protein may be essential for maximizing the tumor suppressor activity and the immunosurveillance functions of IRF-1 in breast epithelial cells.
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Affiliation(s)
| | - A. Catharine Ross
- To whom correspondence should be addressed at Department of Nutritional Sciences, 126-S Henderson Building, University Park, PA 16802.
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Lucken-Ardjomande S, Martinou JC. Regulation of Bcl-2 proteins and of the permeability of the outer mitochondrial membrane. C R Biol 2005; 328:616-31. [PMID: 15992745 DOI: 10.1016/j.crvi.2005.05.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2005] [Accepted: 05/03/2005] [Indexed: 12/12/2022]
Abstract
In many apoptotic responses, pro-apoptotic members of the Bcl-2 family trigger the permeabilization of the outer mitochondrial membrane, thereby allowing the release of mitochondrial apoptogenic factors that contribute to caspase activation in the cytosol. The mechanisms that lead to the activation of pro-apoptotic Bcl-2 family members and to the permeabilization of the outer mitochondrial membrane are not yet completely understood. Here, we attempt to summarize our current view of the mechanisms that lead to these events, regarding both additional proteins that were recently suggested to be involved, and the roles of lipids.
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Affiliation(s)
- Safa Lucken-Ardjomande
- Department of Cell Biology, University of Geneva, 30, quai Ernest-Ansermet, 1211 Genève 4, Switzerland
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Lee KW, Ma L, Yan X, Liu B, Zhang XK, Cohen P. Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXRα/Nur77. J Biol Chem 2005; 280:16942-8. [PMID: 15731112 DOI: 10.1074/jbc.m412757200] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis by its ability to bind insulin-like growth factors (IGFs) as well as its IGF-independent effects involving binding to other molecules including the retinoid X receptor-alpha (RXRalpha). Here we describe that in response to IGFBP-3, the RXRalpha binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation within 6 h. This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells. IGFBP-3 and Nur77 are additive in inducing apoptosis. GFP-Nur77 transfection into RXRalpha wild-type and knock-out mouse embryonic fibroblasts and subsequent treatment with IGFBP-3 show that RXRalpha is required for IGFBP-3-induced Nur77 translocation and apoptosis. Addition of IGFBP-3 to 22RV1 cell lysates enhanced the ability of GST-RXRalpha to "pull down" Nur77, and overexpression of IGFBP-3 enhanced the accumulation of mitochondrial RXRalpha. This unique nongenotropic nuclear pathway supports an emerging role for IGFBP-3 as a novel, multicompartmental signaling molecule involved in induction of apoptosis in malignant cells.
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MESH Headings
- Active Transport, Cell Nucleus
- Animals
- Apoptosis
- Blotting, Western
- Caspases/metabolism
- Cell Nucleus/metabolism
- Cells, Cultured
- Cytoplasm/metabolism
- DNA-Binding Proteins/metabolism
- Densitometry
- Dimerization
- Enzyme Activation
- Enzyme-Linked Immunosorbent Assay
- Fibroblasts/metabolism
- Fluorescent Antibody Technique, Indirect
- Glutathione Transferase/metabolism
- Insulin-Like Growth Factor Binding Protein 3/metabolism
- Insulin-Like Growth Factor Binding Protein 3/physiology
- Mice
- Microscopy, Fluorescence
- Mitochondria/metabolism
- Mutagenesis, Site-Directed
- Nuclear Receptor Subfamily 4, Group A, Member 1
- Protein Transport
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Steroid/metabolism
- Retinoid X Receptor alpha/metabolism
- Signal Transduction
- Somatomedins/metabolism
- Time Factors
- Transcription Factors/metabolism
- Transcription, Genetic
- Transfection
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Affiliation(s)
- Kuk-Wha Lee
- Division of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, David Geffen School of Medicine, Los Angeles, California 90095, USA
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