Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members

Xia, Jun; Liao, Lan; Sarkar, Joy; Matsumoto, Kojiro; Reddy, Janardan K.; Xu, Jianming; Kemper, Byron

doi:10.1016/j.abb.2007.09.005

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…Although GRIP-1 could interact with CAR and HNF4␣ individually, GRIP-1 is not a major player in bridging function. Deletion of the SRC-1, steroid receptor coactivator-2/GRIP-1, and SRC-3/pCIP genes in knockout mice have no effect on CAR-regulated gene transcription (Xia et al, 2007). PBP, on the other hand, acts as a coactivator for CAR, and studies in PBP-null mice indicate that PBP is necessary for the translocation of CAR to the nucleus, and PBP regulates the hepatic expression of CAR (Jia et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor Coactivator 6 Mediates the Synergistic Activation of Human Cytochrome P-450 2C9 by the Constitutive Androstane Receptor and Hepatic Nuclear Factor-4α

et al. 2008

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Nuclear receptor coactivator 6 (NCOA6) also known as PRIP/ RAP250/ASC-2 anchors a steady-state complex of cofactors and function as a transcriptional coactivator for certain nuclear receptors. This is the first study to identify NCOA6 as a hepatic nuclear factor 4␣ (HNF4␣)-interacting protein. CYP2C9 is an important enzyme that metabolizes both commonly used therapeutic drugs and important endogenous compounds. We have shown previously that constitutive androstane receptor (CAR) (a xenobiotic-sensing receptor) up-regulates the CYP2C9 promoter through binding to a distal site, whereas HNF4␣ transcriptionally up-regulates CYP2C9 via proximal sites. We demonstrate ligand-enhanced synergistic cross-talk between CAR and HNF4␣. We identify NCOA6 as crucial to the underlying mechanism of this cross-talk. NCOA6 was identified as an HNF4␣-interacting protein in this study using a yeast two-hybrid screen and GST pull-down assays. Furthermore, we identified NCOA6, CAR, and other coactivators as part of a mega complex of cofactors associated with HNF4␣ in HepG2 cells. Although the interaction of NCOA6 with CAR is specifically through the first LXXLL motif of NCOA6, both LXXLL motifs are involved in its interaction with HNF4␣. Silencing of NCOA6 abrogated the synergistic activation of the CYP2C9 promoter and the synergistic induction of the CYP2C9 gene by CAR-HNF4␣. Chromatin immunoprecipitation analysis revealed that NCOA6 can pull down both the proximal HNF4␣ and distal CAR binding sites of the CYP2C9 promoter and provides the basis for the recruitment of other cofactors. We conclude that the coactivator NCOA6 mediates the mechanism of the synergistic activation of the CYP2C9 gene by CAR and HNF4␣.Cytochrome P450 2C9 (CYP2C9) is a major member of the cytochrome P450 superfamily in human liver, metabolizing numerous therapeutically used drugs and physiologically important endogenous compounds (Goldstein, 2001). Hepatic expression of CYP2C9 exhibits considerable interindividual variability in humans. Some of this interindividual variability is due to the up-regulation of CYP2C9 levels by prior exposure to drugs and xenobiotics such as rifampicin, hyperforin, phenobarbital, and paclitaxel (Taxol) (Raucy et al., 2002;Madan et al., 2003;Komoroski et al., 2004). Studies in primary hepatocytes and clinical studies in vivo in humans have confirmed that CYP2C9 levels and the clearances of CYP2C9 substrates are increased after the administration of drugs (Williamson et al., 1998;Henderson et al., 2002).Recent studies have shown that the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) -(3,4-dichlorobenzyl)oxime; PXR, pregnane X receptor; CREB, cAMP response element-binding pro-

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Section: Discussionmentioning

confidence: 99%

Nuclear Receptor Coactivator 6 Mediates the Synergistic Activation of Human Cytochrome P-450 2C9 by the Constitutive Androstane Receptor and Hepatic Nuclear Factor-4α

et al. 2008

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“…In response to PB and other inducers, CAR is translocated to the nucleus where it forms a functional heterodimer with the retinoid X receptor (RXR). The CAR:RXR heterodimer recruits p160/SRC-1 and other coactivator proteins (Xia et al 2007). The affinity of CAR:RXR heterodimer to coactivators is enhanced by PB-like inducers.…”

Section: Introductionmentioning

confidence: 98%

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

et al. 2009

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“…The three members of p160 coactivators, SRC1, SRC2, and SRC3, as well as PGC1α have been reported to enhance the activity of CAR based on reporter gene assays [52][53][54][55][56][57] . The function of individual coactivators seems to be redundant, at least for the induction of mouse Cyp2b10 [58] . However, an in vivo deficiency of SRC3 impaired TCPOBOP-induced hepatic hyperplasia and drug-metabolizing enzymes, indicating that the coactivation of CAR by different coactivators can be involved in different genomic contexts [59] .…”

Section: Modulators Of Car Activitymentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members

Cited by 10 publications

References 44 publications

Nuclear Receptor Coactivator 6 Mediates the Synergistic Activation of Human Cytochrome P-450 2C9 by the Constitutive Androstane Receptor and Hepatic Nuclear Factor-4α

Nuclear Receptor Coactivator 6 Mediates the Synergistic Activation of Human Cytochrome P-450 2C9 by the Constitutive Androstane Receptor and Hepatic Nuclear Factor-4α

Species-specific induction of CYP2B by 2,4,6-tryphenyldioxane-1,3 (TPD)

Deciphering the roles of the constitutive androstane receptor in energy metabolism

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