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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
2012
Source PublicationJOURNAL OF HEPATOLOGY
ISSN0168-8278
Volume56Issue:1Pages:210-217
Abstract

Background & Aims

Nuclear 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.

Methods

The 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.

Results

SRC-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.

Conclusions

Our 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.

KeywordSrc-3 Car Hepatocyte Proliferation Drug Metabolism
DOIhttps://doi.org/10.1016/j.jhep.2011.07.015
Indexed BySCI
Language英语
WOS Research AreaGastroenterology & Hepatology
WOS SubjectGastroenterology & Hepatology
WOS IDWOS:000298484500034
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Cited Times [WOS]:9   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorChundong Yu
Affiliation1.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.,...&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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