Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk

References

• Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol. 1999;56:1329–1339.
   PubMed Web of Science ®Google Scholar
• Honkakoski P, Zelko I, Sueyoshi T, et al. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol. 1998;18:5652–5658.
   PubMed Web of Science ®Google Scholar
• Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998;92:73–82.
   PubMed Web of Science ®Google Scholar
• Wei P, Zhang J, Egan-Hafley M, et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 2000;407:920–923.
   PubMed Web of Science ®Google Scholar
• Maglich JM, Stoltz CM, Goodwin B, et al. Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol. 2002;62:638–646.
   PubMed Web of Science ®Google Scholar
• Rosenfeld JM, Vargas R Jr, Xie W, et al. Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol Endocrinol. 2003;17:1268–1282.
   PubMed Web of Science ®Google Scholar
• Ueda A, Hamadeh HK, Webb HK, et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol. 2002;61:1–6.
   PubMed Web of Science ®Google Scholar
• Wang H, Faucette S, Sueyoshi T, et al. A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem. 2003;278:14146–14152.
   PubMed Web of Science ®Google Scholar
• Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–839.
   PubMed Web of Science ®Google Scholar
• Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol Sci. 2000;21:381–388.
   PubMed Web of Science ®Google Scholar
• Lehmann JM, McKee DD, Watson MA, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Investig. 1998;102:1016–1023.
   PubMed Web of Science ®Google Scholar
• Teng S, Jekerle V, Piquette-Miller M. Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos. 2003;31:1296–1299.
   PubMed Web of Science ®Google Scholar
• Li T, Chen W, Chiang JY. PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine. J Lipid Res. 2007;48:373–384.
   PubMed Web of Science ®Google Scholar
• Sun M, Cui W, Woody SK, et al. Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes. Drug Metab Dispos. 2015;43:335–343.
   PubMed Web of Science ®Google Scholar
• Watkins RE, Wisely GB, Moore LB, et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science. 2001;292:2329–2333.
   PubMed Web of Science ®Google Scholar
• Orans J, Teotico DG, Redinbo MR. The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol. 2005;19:2891–2900.
   PubMed Web of Science ®Google Scholar
• Zhuo W, Hu L, Lv J, et al. Role of pregnane X receptor in chemotherapeutic treatment. Cancer Chemother Pharmacol. 2014;74:217–227.
   PubMed Web of Science ®Google Scholar
• Zhang B, Xie W, Krasowski MD. PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics. 2008;9:1695–1709.
   PubMed Web of Science ®Google Scholar
• Zucchini N, de Sousa G, Bailly-Maitre B, et al. Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes. Biochim Biophys Acta. 2005;1745:48–58.
   PubMed Web of Science ®Google Scholar
• Masuyama H, Nakatsukasa H, Takamoto N, et al. Down-regulation of pregnane X receptor contributes to cell growth inhibition and apoptosis by anticancer agents in endometrial cancer cells. Mol Pharmacol. 2007;72:1045–1053.
   PubMed Web of Science ®Google Scholar
• Dring MM, Goulding CA, Trimble VI, et al. The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology. 2006;130:341–348.
   PubMed Web of Science ®Google Scholar
• Langmann T, Moehle C, Mauerer R, et al. Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology. 2004;127:26–40.
   PubMed Web of Science ®Google Scholar
• Gupta D, Venkatesh M, Wang H, et al. Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer. Clin Cancer Res. 2008;14:5332–5340.
   PubMed Web of Science ®Google Scholar
• Wang H, Venkatesh M, Li H, et al. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J Clin Invest. 2011;121:3220–3232.
   PubMed Web of Science ®Google Scholar
• Bookout AL, Jeong Y, Downes M, et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006;126:789–799.
   PubMed Web of Science ®Google Scholar
• Wright E, Busby SA, Wisecarver S, et al. Helix 11 dynamics is critical for constitutive androstane receptor activity. Structure. 2011;19:37–44.
   PubMed Web of Science ®Google Scholar
• Li H, Wang H. Activation of xenobiotic receptors: driving into the nucleus. Expert Opin Drug Metab Toxicol. 2010;6:409–426.
   PubMed Web of Science ®Google Scholar
• Locker J, Tian J, Carver R, et al. A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology. 2003;38:314–325.
   PubMed Web of Science ®Google Scholar
• Columbano A, Ledda-Columbano GM, Pibiri M, et al. Gadd45 beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology. 2005;42:1118–1126.
   PubMed Web of Science ®Google Scholar
• Hu X, Lazar MA. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature. 1999;402:93–96.
   PubMed Web of Science ®Google Scholar
• Wu XY, Li H, Park EJ, et al. SMRTe inhibits MEF2C transcriptional activation by targeting HDAC4 and 5 to nuclear domains. J Biol Chem. 2001;276:24177–24185.
   PubMed Web of Science ®Google Scholar
• Johnson DR, Li CW, Chen LY, et al. Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol Pharmacol. 2006;69:99–108.
   PubMed Web of Science ®Google Scholar
• Wang CY, Li CW, Chen JD, et al. Structural model reveals key interactions in the assembly of the pregnane X receptor/corepressor complex. Mol Pharmacol. 2006;69:1513–1517.
   PubMed Web of Science ®Google Scholar
• Konno Y, Kodama S, Moore R, et al. Nuclear xenobiotic receptor pregnane X receptor locks corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D(3) activation. Mol Pharmacol. 2009;75:265–271.
   PubMed Web of Science ®Google Scholar
• Sidhu JS, Omiecinski CJ. Forskolin-mediated induction of CYP3A1 mRNA expression in primary rat hepatocytes is independent of elevated intracellular cyclic AMP. J Pharmacol Exp Ther. 1996;276:238–245.
   PubMed Web of Science ®Google Scholar
• Ding X, Staudinger JL. Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway. J Pharmacol Exp Ther. 2005;312:849–856.
   PubMed Web of Science ®Google Scholar
• Lichti-Kaiser K, Xu CS, Staudinger JL. Cyclic AMP-dependent protein kinase signaling modulates pregnane x receptor activity in a species-specific manner. J Biol Chem. 2009;284:6639–6649.
   PubMed Web of Science ®Google Scholar
• Abdelrazzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome-P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993;44:707–715.
   PubMed Web of Science ®Google Scholar
• Muntanerelat J, Ourlin JC, Domergue J, et al. Differential-effects of cytokines on the inducible expression of Cyp1a1, Cyp1a2, and Cyp3a4 in human hepatocytes in primary culture. Hepatology. 1995;22:1143–1153.
   PubMed Web of Science ®Google Scholar
• Bankey P, Carlson A, Ortiz M, et al. Tumor-necrosis-factor production by kupffer cells requires protein-kinase-C activation. J Surg Res. 1990;49:256–261.
   PubMed Web of Science ®Google Scholar
• Ding XS, Staudinger JL. Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. Biochem Pharmacol. 2005;69:867–873.
   PubMed Web of Science ®Google Scholar
• Lichti-Kaiser K, Brobst D, Xu CS, et al. A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J Pharmacol Exp Ther. 2009;331:65–76.
   PubMed Web of Science ®Google Scholar
• Sugatani J, Uchida T, Kurosawa M, et al. Regulation of Pregnane X Receptor (PXR) function and UGT1A1 gene expression by posttranslational modification of PXR protein. Drug Metab Dispos. 2012;40:2031–2040.
   PubMed Web of Science ®Google Scholar
• Pondugula SR, Brimer-Cline C, Wu J, et al. A phosphomimetic mutation at threonine-57 abolishes transactivation activity and alters nuclear localization pattern of human pregnane X receptor. Drug Metab Dispos. 2009;37:719–730.
   PubMed Web of Science ®Google Scholar
• Rizzo G, Renga B, Antonelli E, et al. The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol. 2005;68:551–558.
   PubMed Web of Science ®Google Scholar
• Qi C, Chang J, Zhu YW, et al. Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor alpha. J Biol Chem. 2002;277:28624–28630.
   PubMed Web of Science ®Google Scholar
• Chen DG, Ma H, Hong H, et al. Regulation of transcription by a protein methyltransferase. Science. 1999;284:2174–2177.
   PubMed Web of Science ®Google Scholar
• Koh SS, Chen DG, Lee YH, et al. Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities. J Biol Chem. 2001;276:1089–1098.
   PubMed Web of Science ®Google Scholar
• Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–45.
   PubMed Web of Science ®Google Scholar
• Xie Y, Ke S, Ouyang NT, et al. Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1. J Biol Chem. 2009;284:9199–9205.
   PubMed Web of Science ®Google Scholar
• Li T, Kong AT, Ma Z, et al. Protein arginine methyltransferase 1 may be involved in pregnane x receptor-activated overexpression of multidrug resistance 1 gene during acquired multidrug resistant. Oncotarget. 2016;7:20236–20248.
   PubMed Web of Science ®Google Scholar
• Onate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the steroid-hormone receptor superfamily. Science. 1995;270:1354–1357.
   PubMed Web of Science ®Google Scholar
• Cavailles V, Dauvois S, Lhorset F, et al. Nuclear factor rip140 modulates transcriptional activation by the estrogen-receptor. Embo Journal. 1995;14:3741–3751.
   PubMed Web of Science ®Google Scholar
• Lee JW, Ryan F, Swaffield JC, et al. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature. 1995;374:91–94.
   PubMed Web of Science ®Google Scholar
• Masuyama H, Hiramatsu Y, Kunitomi M, et al. Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription. Mol Endocrinol. 2000;14:421–428.
   PubMed Web of Science ®Google Scholar
• Ding XS, Lichti K, Staudinger JL. The mycoestrogen zearalenone induces CYP3A through activation of the pregnane X receptor. Toxicological Sci. 2006;91:448–455.
   PubMed Web of Science ®Google Scholar
• Navaratnarajah P, Steele BL, Redinbo MR, et al. Rifampicin-Independent Interactions between the pregnane X receptor ligand binding domain and peptide fragments of coactivator and corepressor proteins. Biochemistry. 2012;51:19–31.
   PubMed Web of Science ®Google Scholar
• Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Investig. 2002;109:1125–1131.
   PubMed Web of Science ®Google Scholar
• Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–340.
   PubMed Web of Science ®Google Scholar
• Roth A, Looser R, Kaufmann M, et al. Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes. Pharmacogenet Genomics. 2008;18:325–337.
   PubMed Web of Science ®Google Scholar
• Lin JD, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1:361–370.
   PubMed Web of Science ®Google Scholar
• Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Investig. 2006;116:615–622.
   PubMed Web of Science ®Google Scholar
• Pascussi JM, Gerbal-Chaloin S, Duret C, et al. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol. 2008;48:1–32.
   PubMed Web of Science ®Google Scholar
• Bhalla S, Ozalp C, Fang SS, et al. Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1 alpha - Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem. 2004;279:45139–45147.
   PubMed Web of Science ®Google Scholar
• Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9:799–809.
   PubMed Web of Science ®Google Scholar
• Baert FJ, D’Haens GR, Peeters M, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology. 1999;116:22–28.
   PubMed Web of Science ®Google Scholar
• Tamion F, Richard V, Lyoumi S, et al. Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock. Am J Physiology-Gastrointestinal Liver Physiol. 1997;273:G314–G21.
   PubMed Web of Science ®Google Scholar
• Brown GR, Lindberg G, Meddings J, et al. Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease. Gastroenterology. 1999;116:593–601.
   PubMed Web of Science ®Google Scholar
• Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol. 2002;97:2000–2004.
   PubMed Web of Science ®Google Scholar
• Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129:550–564.
   PubMed Web of Science ®Google Scholar
• Zeissig S, Burgel N, Gunzel D, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007;56:61–72.
   PubMed Web of Science ®Google Scholar
• Blair SA, Kane SV, Clayburgh DR, et al. Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab Investig. 2006;86:191–201.
   PubMed Web of Science ®Google Scholar
• Duerksen DR, Wilhelm-Boyles C, Parry DM. Intestinal permeability in long-term follow-up of patients with celiac disease on a gluten-free diet. Dig Dis Sci. 2005;50:785–790.
   PubMed Web of Science ®Google Scholar
• Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA. 2009;106:3698–3703.
   PubMed Web of Science ®Google Scholar
• Venkatesh M, Mukherjee S, Wang HW, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4. Immunity. 2014;41:296–310.
   PubMed Web of Science ®Google Scholar
• Shah P, Guo T, Moore DD, et al. Role of constitutive androstane receptor in toll-like receptor-mediated regulation of gene expression of hepatic drug-metabolizing enzymes and transporters. Drug Metab Dispos. 2014;42:172–181.
   PubMed Web of Science ®Google Scholar
• Ghose R, Mallick P, Taneja G, et al. In vitro approaches to study regulation of hepatic cytochrome P450 (CYP) 3A expression by paclitaxel and rifampicin. Methods Mol Biol. 2016;1395:55–68.
   PubMedGoogle Scholar
• Elias A, Wu J, Chen T. Tumor suppressor protein p53 negatively regulates human pregnane X receptor activity. Mol Pharmacol. 2013;83:1229–1236.
   PubMed Web of Science ®Google Scholar
• Zhou J, Liu M, Zhai Y, et al. The antiapoptotic role of pregnane X receptor in human colon cancer cells. Mol Endocrinol. 2008;22:868–880.
   PubMed Web of Science ®Google Scholar
• Robbins D, Cherian M, Wu J, et al. Human pregnane X receptor compromises the function of p53 and promotes malignant transformation. Cell Death Discov. 2016;2:16023.
   PubMed Web of Science ®Google Scholar
• Ouyang N, Ke S, Eagleton N, et al. Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells. Br J Cancer. 2010;102:1753–1761.
   PubMed Web of Science ®Google Scholar
• Verma S, Tabb MM, Blumberg B. Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells. BMC Cancer. 2009;9:3.
   PubMed Web of Science ®Google Scholar
• Brune B. The intimate relation between nitric oxide and superoxide in apoptosis and cell survival. Antioxid Redox Signal. 2005;7:497–507.
   PubMed Web of Science ®Google Scholar
• Yang F, von Knethen A, Brune B. Modulation of nitric oxide-evoked apoptosis by the p53-downstream target p21(WAF1/CIP1). J Leukoc Biol. 2000;68:916–922.
   PubMed Web of Science ®Google Scholar
• Robbins D, Bakke J, Cherian MT, et al. PXR interaction with p53: a meeting of two masters. Cell Death Dis. 2016;7:e2218.
   Google Scholar
• Paunescu E. In vivo and in vitro suppression of humoral and cellular immunological response by rifampicin. Nature. 1970;228:1188–1190.
   PubMed Web of Science ®Google Scholar
• Pascussi JM, Gerbal-Chaloin S, Pichard-Garcia L, et al. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem Biophys Res Commun. 2000;274:707–713.
   PubMed Web of Science ®Google Scholar
• Yang J, Hao C, Yang D, et al. Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes. Toxicol Lett. 2010;197:219–226.
   PubMed Web of Science ®Google Scholar
• Gu X, Ke S, Liu D, et al. Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem. 2006;281:17882–17889.
   PubMed Web of Science ®Google Scholar
• Xie W, Tian Y. Xenobiotic receptor meets NF-kappaB, a collision in the small bowel. Cell Metab. 2006;4:177–178.
   PubMed Web of Science ®Google Scholar
• Zhou C, Tabb MM, Nelson EL, et al. Mutual repression between steroid and xenobiotic receptor and NF-kappa B signaling pathways links xenobiotic metabolism and inflammation. J Clin Investig. 2006;116:2280–2289.
   PubMed Web of Science ®Google Scholar
• Martinez SC, Cras-Meneur C, Bernal-Mizrachi E, et al. Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell. Diabetes. 2006;55:1581–1591.
   PubMed Web of Science ®Google Scholar
• Kodama S, Koike C, Negishi M, et al. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol. 2004;24:7931–7940.
   PubMed Web of Science ®Google Scholar
• Kodama S, Moore R, Yamamoto Y, et al. Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene. Biochem J. 2007;407:373–381.
   PubMed Web of Science ®Google Scholar
• Gotoh S, Negishi M. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci Rep. 2015;5:14076.
   PubMed Web of Science ®Google Scholar
• Gotoh S, Negishi M. Serum- and glucocorticoid-regulated kinase 2 determines drug-activated pregnane X receptor to induce gluconeogenesis in human liver cells. J Pharmacol Exp Ther. 2014;348:131–140.
   PubMed Web of Science ®Google Scholar
• Shizu R, Abe T, Benoki S, et al. PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor. Biochem J. 2016;473:257–266.
   PubMed Web of Science ®Google Scholar
• Pondugula SR, Xie W, Chen T. PXR and hepatocyte proliferation. J Exp Clin Med. 2010;2:260–261.
   Google Scholar
• Iwazaki N, Kobayashi K, Morimoto K, et al. Involvement of hepatocyte nuclear factor 4 alpha in transcriptional regulation of the human pregnane X receptor gene in the human liver. Drug Metab Pharmacokinet. 2008;23:59–66.
   PubMed Web of Science ®Google Scholar
• Zhang S, Pan X, Jeong H. GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. Drug Metab Dispos. 2015;43:743–748.
   PubMed Web of Science ®Google Scholar
• Burk O, Koch I, Raucy J, et al. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem. 2004;279:38379–38385.
   PubMed Web of Science ®Google Scholar
• Noll EM, Eisen C, Stenzinger A, et al. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med. 2016;22:278–287.
   PubMed Web of Science ®Google Scholar
• Westlind-Johnsson A, Malmebo S, Johansson A, et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos. 2003;31:755–761.
   PubMed Web of Science ®Google Scholar
• Ong SS, Goktug AN, Elias A, et al. Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2. Biochem J. 2014;459:193–203.
   PubMed Web of Science ®Google Scholar
• Kim SW, Hasanuzzaman M, Cho M, et al. Casein kinase 2 (CK2)-mediated phosphorylation of Hsp90beta as a novel mechanism of rifampin-induced MDR1 expression. J Biol Chem. 2015;290:17029–17040.
   PubMed Web of Science ®Google Scholar
• Elias A, High AA, Mishra A, et al. Identification and characterization of phosphorylation sites within the pregnane X receptor protein. Biochem Pharmacol. 2014;87:360–370.
   PubMed Web of Science ®Google Scholar
• Lin W, Wu J, Dong H, et al. Cyclin-dependent kinase 2 negatively regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells. J Biol Chem. 2008;283:30650–30657.
   PubMed Web of Science ®Google Scholar
• Pondugula SR, Tong AA, Wu J, et al. Protein phosphatase 2Cbetal regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells. Drug Metab Dispos. 2010;38:1411–1416.
   PubMed Web of Science ®Google Scholar
• Pasquel D, Doricakova A, Li H, et al. Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity. Biochim Biophys Acta. 2016. doi:10.1016/j.bbagrm.2016.01.006.
   PubMedGoogle Scholar
• Smith RP, Eckalbar WL, Morrissey KM, et al. Genome-wide discovery of drug-dependent human liver regulatory elements. PLoS Genet. 2014;10:e1004648.
   PubMedGoogle Scholar
• Cui W, Sun M, Zhang S, et al. A SUMO-acetyl switch in PXR biology. Biochim Biophys Acta. 2016. doi:10.1016/j.bbagrm.2016.02.008.
   Google Scholar
• Masahiko N, Honkakoski P. Induction of drug metabolism by nuclear receptor CAR: molecular mechanisms and implications for drug research. Eur J Pharm Sci. 2000;11:259–264.
   PubMed Web of Science ®Google Scholar
• Yoshinari K, Kobayashi K, Moore R, et al. Identification of the nuclear receptor CAR: HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Lett. 2003;548:17–20.
   PubMed Web of Science ®Google Scholar
• Kobayashi K, Sueyoshi T, Inoue K, et al. Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol. 2003;64:1069–1075.
   PubMed Web of Science ®Google Scholar
• Osabe M, Negishi M. Active ERK1/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR; NR1I3), repressing dephosphorylation and sequestering CAR in the cytoplasm. J Biol Chem. 2011;286:35763–35769.
   PubMed Web of Science ®Google Scholar
• Mutoh S, Osabe M, Inoue K, et al. Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3). J Biol Chem. 2009;284:34785–34792.
   PubMed Web of Science ®Google Scholar
• Zelko I, Sueyoshi T, Kawamoto T, et al. The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver. Mol Cell Biol. 2001;21:2838–2846.
   PubMed Web of Science ®Google Scholar
• Mutoh S, Sobhany M, Moore R, et al. Phenobarbital indirectly activates the Constitutive Active Androstane Receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal. 2013;6:ra31.
   PubMed Web of Science ®Google Scholar
• Kaestner KH, Knöchel W, Martínez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000;14:142–146.
   PubMed Web of Science ®Google Scholar
• Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–7425.
   PubMed Web of Science ®Google Scholar
• Barthel A, Schmoll D, Unterman TG. FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab. 2005;16:183–189.
   PubMed Web of Science ®Google Scholar
• Stahl M, Dijkers PF, Kops GJ, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 2002;168:5024–5031.
   PubMed Web of Science ®Google Scholar
• Nakae J, Kitamura T, Silver DL, et al. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest. 2001;108:1359–1367.
   PubMed Web of Science ®Google Scholar
• Zhang W, Patil S, Chauhan B, et al. FoxO1 regulates multiple metabolic pathways in the liver effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006;281:10105–10117.
   PubMed Web of Science ®Google Scholar
• Kodama S, Koike C, Negishi M, et al. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol. 2004;24:7931–7940.
   PubMed Web of Science ®Google Scholar
• Manenti G, Dragani TA, Della Porta G. Effects of phenobarbital and 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene on differentiated functions in mouse liver. Chem Biol Interact. 1987;64:83–92.
   PubMed Web of Science ®Google Scholar
• Kazantseva YA, Yarushkin AA, Pustylnyak VO. CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers. Toxicology. 2014;321:73–79.
   PubMed Web of Science ®Google Scholar
• Roth A, Looser R, Kaufmann M, et al. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol. 2008;73:1282–1289.
   PubMed Web of Science ®Google Scholar
• Gao J, He J, Zhai Y, et al. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem. 2009;284:25984–25992.
   PubMed Web of Science ®Google Scholar
• Puigserver P, Wu Z, Park CW, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
   PubMed Web of Science ®Google Scholar
• Puigserver P. Spiegelman BM Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78–90.
   PubMed Web of Science ®Google Scholar
• Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature. 2005;434:113–118.
   PubMed Web of Science ®Google Scholar
• Michael LF, Wu Z, Cheatham RB, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci. 2001;98:3820–3825.
   PubMed Web of Science ®Google Scholar
• Shiraki T, Sakai N, Kanaya E, et al. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor γ coactivator-1α A POSSIBLE LINK BETWEEN XENOBIOTIC RESPONSE AND NUTRITIONAL STATE. J Biol Chem. 2003;278:11344–11350.
   PubMed Web of Science ®Google Scholar
• Gao J, Yan J, Xu M, et al. CAR suppresses hepatic gluconeogenesis by facilitating the ubiquitination and degradation of PGC1α. Mol Endocrinol. 2015;29:1558–1570.
   PubMed Web of Science ®Google Scholar
• Miao J, Fang S, Bae Y, et al. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1α. J Biol Chem. 2006;281:14537–14546.
   PubMed Web of Science ®Google Scholar
• Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature. 2003;423:550–555.
   PubMed Web of Science ®Google Scholar
• Dong B, Saha PK, Huang W, et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci. 2009;106:18831–18836.
   PubMed Web of Science ®Google Scholar
• Leo C, Chen JD. The SRC family of nuclear receptor coactivators. Gene. 2000;245:1–11.
   PubMed Web of Science ®Google Scholar
• Heery DM, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997;387:733–736.
   PubMed Web of Science ®Google Scholar
• Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-β. Nature. 1998;395:612–615.
   PubMed Web of Science ®Google Scholar
• Pavlin MR, Brunzelle JS, Fernandez EJ. Agonist ligands mediate the transcriptional response of nuclear receptor heterodimers through distinct stoichiometric assemblies with coactivators. J Biol Chem. 2014;289:24771–24778.
   PubMed Web of Science ®Google Scholar
• Muangmoonchai R, Smirlis D, Siew-Cheng W, et al. Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1. Biochem J. 2001;355:71–78.
   PubMed Web of Science ®Google Scholar
• Min G, Kemper JK, Kemper B. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J Biol Chem. 2002;277:26356–26363.
   PubMed Web of Science ®Google Scholar
• Xia J, Liao L, Sarkar J, et al. Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members. Arch Biochem Biophys. 2007;468:49–57.
   PubMed Web of Science ®Google Scholar
• Chen T, Chen Q, Xu Y, et al. SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism. J Hepatol. 2012;56:210–217.
   PubMed Web of Science ®Google Scholar
• Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995;377:454–457.
   PubMed Web of Science ®Google Scholar
• Hörlein AJ, Näär AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377:397–404.
   PubMed Web of Science ®Google Scholar
• Alland L, Muhle R, Hou H Jr, et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997;387:49–55.
   PubMed Web of Science ®Google Scholar
• Nagy L, Kao HY, Chakravarti D, et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997;89:373–380.
   PubMed Web of Science ®Google Scholar
• Park E-J, Schroen DJ, Yang M, et al. SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor. Proc Natl Acad Sci. 1999;96:3519–3524.
   PubMed Web of Science ®Google Scholar
• Dussault I, Lin M, Hollister K, et al. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol Cell Biol. 2002;22:5270–5280.
   PubMed Web of Science ®Google Scholar
• Mäkinen J, Frank C, Jyrkkärinne J, et al. Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol Pharmacol. 2002;62:366–378.
   PubMed Web of Science ®Google Scholar
• Lempiäinen H, Molnár F, Macias Gonzalez M, et al. Antagonist-and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. Mol Endocrinol. 2005;19:2258–2272.
   PubMed Web of Science ®Google Scholar
• Niakan K, McCabe E. DAX1 origin, function, and novel role. Mol Genet Metab. 2005;86:70–83.
   PubMed Web of Science ®Google Scholar
• Crawford PA, Dorn C, Sadovsky Y, et al. Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol. 1998;18:2949–2956.
   PubMed Web of Science ®Google Scholar
• Laurenzana EM, Chen T, Kannuswamy M, et al. The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3). Mol Pharmacol. 2012;82:918–928.
   PubMed Web of Science ®Google Scholar
• Maglich JM, Parks DJ, Moore LB, et al. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J Biol Chem. 2003;278:17277–17283.
   PubMed Web of Science ®Google Scholar
• Seol WG, Moore DD. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimarizes with other receptors. Science. 1996;272:308–311.
   Web of Science ®Google Scholar
• Bae Y, Kemper JK, Kemper B. Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol. 2004;23:81–91.
   PubMed Web of Science ®Google Scholar
• Zhan Q, Lord KA, Alamo I, et al. The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol. 1994;14:2361–2371.
   PubMed Web of Science ®Google Scholar
• Papa S, Zazzeroni F, Bubici C, et al. Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol. 2004;6:146–153.
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Moore R, Flavell RA, et al. Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS One. 2010;5:e10121.
   PubMedGoogle Scholar
• Yamamoto Y, Moore R, Goldsworthy TL, et al. The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res. 2004;64:7197–7200.
   PubMed Web of Science ®Google Scholar
• Smutny T, Mani S, Pavek P. Post-translational and post-transcriptional modifications of Pregnane X Receptor (PXR) in regulation of the cytochrome P450 superfamily. Curr Drug Metab. 2013;14:1059–1069.
   PubMed Web of Science ®Google Scholar
• Li F, Lu J, Cheng J, et al. Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy. Nat Med. 2013;19:418–420.
   PubMed Web of Science ®Google Scholar
• Serrou B, Solassol C, Joyeux H, et al. Immunosuppressive effect of rifampicin. Transplantation. 1972;14:654–655.
   PubMed Web of Science ®Google Scholar
• Litwin A, Brooks SM, Claes F. A pilot study concerning the early immunosuppressive effects of rifampin in man. Chest. 1974;65:548–551.
   PubMed Web of Science ®Google Scholar