The major human Pregnane X Receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation

Drug Metabolism and Disposition

Volumn 37, Issue 6, 2009, Pages 1295-1304

  Lin, Yvonne S ^a,c   Yasuda, Kazuto ^a   Assem, Mahfoud ^a,d   Cline, Cynthia ^a   Barber, Joe ^a   Li, Chia Wei ^b,e   Kholodovych, Vladyslav ^b   Ai, Ni ^b   Chen, J Don ^b   Welsh, William J ^b   Ekins, Sean ^b   Schuetz, Erin G ^a  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^b RUTGERS ROBERT WOOD JOHNSON MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF WASHINGTON   (United States)

^d UNIVERSITY OF IOWA   (United States)

^e UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 3A4; PREGNANE X RECEPTOR;

ALTERNATIVE RNA SPLICING; ARTICLE; CELL STRAIN HEPG2; CONTROLLED STUDY; HUMAN; HUMAN CELL; LIGAND BINDING; MOLECULAR MODEL; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN VARIANT; SEQUENCE HOMOLOGY; TRANSACTIVATION; TRANSCRIPTION REGULATION;

ALTERNATIVE SPLICING; CATALYTIC DOMAIN; CYTOCHROME P-450 CYP3A; GENE EXPRESSION REGULATION; GENES, REPORTER; HUMANS; MICROSOMES, LIVER; PROMOTER REGIONS, GENETIC; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN ISOFORMS; RECEPTORS, STEROID; RIFAMPIN; TRANSCRIPTIONAL ACTIVATION; TRANSFECTION; TUMOR CELLS, CULTURED;

EID: 66649086262     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.108.025213     Document Type: Article

References (40)

1. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, and Berkenstam A (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95:12208-12213. (Pubitemid 28483744)
2. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, and Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195-3205. (Pubitemid 28496264)
3. Carnahan VE and Redinbo MR (2005) Structure and function of the human nuclear xenobiotic receptor PXR. Curr Drug Metab 6:357-367. (Pubitemid 41086768)
4. Chrencik JE, Orans J, Moore LB, Xue Y, Peng L, Collins JL, Wisely GB, Lambert MH, Kliewer SA, and Redinbo MR (2005) Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 19:1125-1134. (Pubitemid 40594113)
5. Ciesielski F, Rochel N, and Moras D (2007) Adaptability of the vitamin D nuclear receptor to the synthetic ligand gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol 103:235-242. (Pubitemid 46401297)
6. Dotzlaw H, Leygue E, Watson P, and Murphy LC (1999) The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin Cancer Res 5:2103-2107. (Pubitemid 29399265)
7. Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, et al. (2003) A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11:1079-1092. (Pubitemid 36566328)
8. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, et al. (2001) Intrinsically disordered protein. J Mol Graph Model 19:26-59. (Pubitemid 32411501)
9. Ekins S, Mirny L, and Schuetz EG (2002) A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXRa and LXRb. Pharm Res 19:1788-1800. (Pubitemid 36016024)
10. Ekins S, Reschly EJ, Hagey LR, and Krasowski MD (2008) Evolution of pharmacologic specificity in the pregnane X receptor. BMC Evol Biol 8:103-124.
11. Fishman MC and Kirby ML (1998) The human orphan receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1-8.
12. Fukuen S, Fukuda T, Matsuda H, Sumida A, Yamamoto I, Inaba T, and Azuma J (2002) Identification of the novel splicing variants for the hPXR in human livers. Biochem Biophys Res Commun 298:433-438. (Pubitemid 35333725)
13. Gardner-Stephen D, Heydel JM, Goyal A, Lu Y, Xie W, Lindblom T, Mackenzie P, and Radominska-Pandya A (2004) Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression. Drug Metab Dispos 32:340-347. (Pubitemid 38263893)
14. Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, et al. (2001) Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 29:1454-1459. (Pubitemid 33000692)
15. Johnson DR, Li CW, Chen LY, Ghosh JC, and Chen JD (2006) Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol Pharmacol 69:99-108. (Pubitemid 43048897)
16. Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, et al. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14:27-39. (Pubitemid 32260325)
17. Kim HJ, Woo IS, Kang ES, Eun SY, Kim HJ, Lee JH, Chang KC, Kim JH, and Seo HG (2006) Identification of a truncated alternative splicing variant of human PPARgamma1 that exhibits dominant negative activity. Biochem Biophys Res Commun 347:698-706. (Pubitemid 44092640)
18. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterström RH, et al. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73-82. (Pubitemid 28053299)
19. Kliewer SA and Willson TM (2002) Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J Lipid Res 43:359-364. (Pubitemid 34252265)
20. Krasowski MD, Reschly EJ, and Ekins S (2008) Intrinsic disorder in nuclear hormone receptors. J Proteome Res 7:4359-4372.
21. Krasowski MD, Yasuda K, Hagey LR, and Schuetz EG (2005a) Evolution of the pregnane X receptor: adaptation to cross-species differences in biliary bile salts. Mol Endocrinol 19:1720-1739. (Pubitemid 41007886)
22. Krasowski MD, Yasuda K, Hagey LR, and Schuetz EG (2005b) Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors). Nucl Recept 3:2. (Pubitemid 41522382)
23. Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, and Schuetz EG (2004) PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol 199:251-265. (Pubitemid 39208725)
24. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, et al. (2003) Identification of a novel human CAR agonist and its use in the identification of CAR target genes. J Biol Chem 278:17277-17283.
25. Moore JT, Moore LB, Maglich JM, and Kliewer SA (2003) Functional and structural comparison of PXR and CAR. Biochim Biophys Acta 1619:235-238. (Pubitemid 36160601)
26. Noble SM, Carnahan VE, Moore LB, Luntz T, Wang H, Ittoop OR, Stimmel JB, Davis-Searles PR, Watkins RE, Wisely GB, et al. (2006) Human PXR forms a tryptophan zipper-mediated homodimer. Biochemistry 45:8579-8589. (Pubitemid 44078878)
27. Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, and Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3:35-60. (Pubitemid 40305483)
28. Reschly EJ, Ai N, Ekins S, Welsh WJ, Hagey LR, Hofmann AF, and Krasowski MD (2008) Evolution of the bile salt nuclear receptor FXR in vertebrates. J Lipid Res 49:1577-1587.
29. Reschly EJ, Bainy AC, Mattos JJ, Hagey LR, Bahary N, Mada SR, Ou J, Venkataramanan R, and Krasowski MD (2007) Functional evolution of the vitamin D and pregnane X receptors. BMC Evol Biol 7:222.
30. Rochel N, Tocchini-Valentini G, Egea PF, Juntunen K, Garnier JM, Vihko P, and Moras D (2001) Functional and structural characterization of the insertion region in the ligand binding domain of the vitamin D nuclear receptor. Eur J Biochem 268:971-979. (Pubitemid 32328341)
31. Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z, et al. (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci U S A 103:8390-8395. (Pubitemid 43838465)
32. Schuetz E and Strom S (2001) Promiscuous regulator of xenobiotic removal. Nat Med 7:536-537. (Pubitemid 32448312)
33. Synold TW, Dussault I, and Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584-590. (Pubitemid 32448326)
34. Teotico DG, Frazier ML, Ding F, Dokholyan NV, Temple BR, and Redinbo MR (2008) Active nuclear receptors exhibit highly correlated AF-2 domain motions. PLoS Comput Biol 4:e1000111.
35. Tirona RG, Leake BF, Podust LM, and Kim RB (2004) Identification of amino acids in rat pregnane X receptor that determine species-specific activation. Mol Pharmacol 65:36-44. (Pubitemid 38113884)
36. Watkins RE, Davis-Searles PR, Lambert MH, and Redinbo MR (2003a) Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 331:815-828. (Pubitemid 36945439)
37. Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, and Redinbo MR (2003b) 2.1A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry 42:1430-1438.
38. Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, and Redinbo MR (2001) The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329-2333. (Pubitemid 32568055)
39. Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, Schuetz E, and Bachmann K (2008) A comprehensive in vitro and in silico analysis of antibiotics that activate PXR and induce CYP3A4 in liver and intestine. Drug Metab Dispos 36:1689-1697.
40. Zhang Y, Kast-Woelbern HR, and Edwards PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278:104-110. (Pubitemid 36043550)