| Residential College | false |
| Status | 已發表Published |
| SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism | |
Tenghui Chen1; Qiang Chen1 ; Yixiang Xu2,3; Qiling Zhou1; Jingwei Zhu1; Hao Zhang4,5; Qiao Wu1; Jianming Xu2,3; Chundong Yu1
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| 2012 | |
| Source Publication | JOURNAL OF HEPATOLOGY
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| ISSN | 0168-8278 |
| Volume | 56Issue:1Pages:210-217 |
| Abstract | Background & AimsNuclear receptors such as pregnane X receptor and constitutive androstane receptor (CAR) are important regulators of drug-metabolizing systems such as P450s enzymes and modulate xenobiotic metabolism as well as hepatocellular proliferation. Binding of CAR to NR response elements alone is not sufficient to activate gene expression. Here we investigate the role of steroid receptor coactivator (SRC) family members in CAR-mediated hepatocyte proliferation and drug metabolism. MethodsThe role of SRCs in CAR activation was assessed in cell-based transfection assays and protein-protein interaction assays. The in vivo role of SRCs in CAR-mediated hepatocyte proliferation and drug metabolism was examined by using mice deficient in SRCs. ResultsSRC-3 displayed the highest coactivating activity to CAR compared with SRC-1 and SRC-2 in a cell-based reporter assay. Knockout of SRC-3 in mice attenuated hepatic hyperplasia induced by a CAR agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), which was associated with a reduced expression of c-Myc and Foxm-1. In contrast, knockout of SRC-1 or SRC-2 in mice did not affect TCPOBOP-induced hepatic hyperplasia. SRC-3-deficient mice were hypersensitive to zoxazolamine-induced paralysis, but were resistant to acetaminophen hepatotoxicity induced by TCPOBOP, whereas mutant mice deficient in SRC-1 or SRC-2 exhibited severe acetaminophen hepatotoxicity similar to wild-type controls. Accordingly, deficiency in SRC-3, but not SRC-1 or SRC-2, resulted in a reduced CAR-mediated expression of drug metabolism-related genes in the liver. ConclusionsOur study demonstrates that SRC-3 is the predominant transcriptional coactivator among the three SRC family members for CAR activation to promote hepatocyte proliferation and drug metabolism. |
| Keyword | Src-3 Car Hepatocyte Proliferation Drug Metabolism |
| DOI | 10.1016/j.jhep.2011.07.015 |
| Indexed By | SCIE |
| Language | 英語English |
| WOS Research Area | Gastroenterology & Hepatology |
| WOS Subject | Gastroenterology & Hepatology |
| WOS ID | WOS:000298484500034 |
| Scopus ID | 2-s2.0-83555174696 |
| Fulltext Access | |
| Citation statistics | |
| Document Type | Journal article |
| Collection | Faculty of Health Sciences DEPARTMENT OF BIOMEDICAL SCIENCES |
| Corresponding Author | Chundong Yu |
| Affiliation | 1.State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China 2.Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA 3.Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA 4.Cancer Research Center at Shantou University Medical College and Department of Integrative Chinese and Western Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China 5.Department of Integrative Chinese and Western Medicine, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China |
| Recommended Citation GB/T 7714 | Tenghui Chen,Qiang Chen,Yixiang Xu,et al. SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism[J]. JOURNAL OF HEPATOLOGY, 2012, 56(1), 210-217. |
| APA | Tenghui Chen., Qiang Chen., Yixiang Xu., Qiling Zhou., Jingwei Zhu., Hao Zhang., Qiao Wu., Jianming Xu., & Chundong Yu (2012). SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism. JOURNAL OF HEPATOLOGY, 56(1), 210-217. |
| MLA | Tenghui Chen,et al."SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism".JOURNAL OF HEPATOLOGY 56.1(2012):210-217. |
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