- Constitutive androstane receptor
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The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene.[1] CAR is a member of the nuclear receptor superfamily and along with PXR functions as a sensor of endobiotic and xenobiotic substances and in response upregulates the expression of proteins responsible for the metabolism and excretion of these substances.[2] Hence CAR (and PXR) are important in the detoxification of foreign substances such as drugs.
Contents
Function
CAR is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs.[3]
References
- ^ Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, Moore DD (March 1994). "A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements". Mol. Cell. Biol. 14 (3): 1544–52. PMC 358513. PMID 8114692. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=358513.
- ^ Wada T, Gao J, Xie W (August 2009). "PXR and CAR in energy metabolism". Trends Endocrinol. Metab. 20 (6): 273–9. doi:10.1016/j.tem.2009.03.003. PMID 19595610.
- ^ "Entrez Gene: NR1I3 nuclear receptor subfamily 1, group I, member 3". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9970.
Further reading
- Masuno M, Shimozawa N, Suzuki Y, et al. (1994). "Assignment of the human peroxisome assembly factor-1 gene (PXMP3) responsible for Zellweger syndrome to chromosome 8q21.1 by fluorescence in situ hybridization". Genomics 20 (1): 141–2. doi:10.1006/geno.1994.1144. PMID 8020947.
- Choi HS, Seol W, Moore DD (1996). "A component of the 26S proteasome binds on orphan member of the nuclear hormone receptor superfamily". J. Steroid Biochem. Mol. Biol. 56 (1–6 Spec No): 23–30. doi:10.1016/0960-0760(95)00220-0. PMID 8603043.
- Seol W, Choi HS, Moore DD (1996). "An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors". Science 272 (5266): 1336–9. doi:10.1126/science.272.5266.1336. PMID 8650544.
- Choi HS, Chung M, Tzameli I, et al. (1997). "Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR". J. Biol. Chem. 272 (38): 23565–71. doi:10.1074/jbc.272.38.23565. PMID 9295294.
- Seol W, Hanstein B, Brown M, Moore DD (1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Mol. Endocrinol. 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
- Forman BM, Tzameli I, Choi HS, et al. (1998). "Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta". Nature 395 (6702): 612–5. doi:10.1038/26996. PMID 9783588.
- Gonzalez MM, Carlberg C (2002). "Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors". J. Biol. Chem. 277 (21): 18501–9. doi:10.1074/jbc.M200205200. PMID 11891224.
- Min G, Kim H, Bae Y, et al. (2002). "Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators". J. Biol. Chem. 277 (37): 34626–33. doi:10.1074/jbc.M205239200. PMID 12114525.
- Goodwin B, Hodgson E, D'Costa DJ, et al. (2002). "Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor". Mol. Pharmacol. 62 (2): 359–65. doi:10.1124/mol.62.2.359. PMID 12130689.
- Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA (2002). "Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site". Mol. Pharmacol. 62 (3): 737–46. doi:10.1124/mol.62.3.737. PMID 12181452.
- Zhang J, Huang W, Chua SS, et al. (2002). "Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR". Science 298 (5592): 422–4. doi:10.1126/science.1073502. PMID 12376703.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Chang TK, Bandiera SM, Chen J (2003). "Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels". Drug Metab. Dispos. 31 (1): 7–10. doi:10.1124/dmd.31.1.7. PMID 12485946.
- Pascussi JM, Busson-Le Coniat M, Maurel P, Vilarem MJ (2003). "Transcriptional analysis of the orphan nuclear receptor constitutive androstane receptor (NR1I3) gene promoter: identification of a distal glucocorticoid response element". Mol. Endocrinol. 17 (1): 42–55. doi:10.1210/me.2002-0244. PMID 12511605.
- Shiraki T, Sakai N, Kanaya E, Jingami H (2003). "Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state". J. Biol. Chem. 278 (13): 11344–50. doi:10.1074/jbc.M212859200. PMID 12551939.
- Maglich JM, Parks DJ, Moore LB, et al. (2003). "Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes". J. Biol. Chem. 278 (19): 17277–83. doi:10.1074/jbc.M300138200. PMID 12611900.
- Xie W, Yeuh MF, Radominska-Pandya A, et al. (2003). "Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4150–5. doi:10.1073/pnas.0438010100. PMC 153063. PMID 12644700. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=153063.
- Huang W, Zhang J, Chua SS, et al. (2003). "Induction of bilirubin clearance by the constitutive androstane receptor (CAR)". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4156–61. doi:10.1073/pnas.0630614100. PMC 153064. PMID 12644704. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=153064.
- Auerbach SS, Ramsden R, Stoner MA, et al. (2003). "Alternatively spliced isoforms of the human constitutive androstane receptor". Nucleic Acids Res. 31 (12): 3194–207. doi:10.1093/nar/gkg419. PMC 162252. PMID 12799447. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=162252.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
PDB gallery 
1xv9: crystal structure of CAR/RXR heterodimer bound with SRC1 peptide, fatty acid, and 5b-pregnane-3,20-dione.
1xvp: crystal structure of CAR/RXR heterodimer bound with SRC1 peptide, fatty acid and CITCOTranscription factors and intracellular receptors (1) Basic domains (1.1) Basic leucine zipper (bZIP)Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) · AP-1 (c-Fos, FOSB, FOSL1, FOSL2, JDP2, c-Jun, JUNB, JUND) · BACH (1, 2) · BATF · BLZF1 · C/EBP (α, β, γ, δ, ε, ζ) · CREB (1, 3, L1) · CREM · DBP · DDIT3 · GABPA · HLF · MAF (B, F, G, K) · NFE (2, L1, L2, L3) · NFIL3 · NRL · NRF (1, 2, 3) · XBP1(1.2) Basic helix-loop-helix (bHLH)ATOH1 · AhR · AHRR · ARNT · ASCL1 · BHLHB2 · BMAL (ARNTL, ARNTL2) · CLOCK · EPAS1 · FIGLA · HAND (1, 2) · HES (5, 6) · HEY (1, 2, L) · HES1 · HIF (1A, 3A) · ID (1, 2, 3, 4) · LYL1 · MESP2 · MXD4 · MYCL1 · MYCN · Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) · Neurogenins (1, 2, 3) · NeuroD (1, 2) · NPAS (1, 2, 3) · OLIG (1, 2) · Pho4 · Scleraxis · SIM (1, 2) · TAL (1, 2) · Twist · USF1(1.3) bHLH-ZIP(1.4) NF-1(1.5) RF-X(1.6) Basic helix-span-helix (bHSH)(2) Zinc finger DNA-binding domains (2.1) Nuclear receptor (Cys4)subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR)
subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX)
subfamily 3 (Steroid hormone (Androgen, Estrogen (α, β), Glucocorticoid, Mineralocorticoid, Progesterone), Estrogen related (α, β, γ))
subfamily 4 NUR (NGFIB, NOR1, NURR1) · subfamily 5 (LRH-1, SF1) · subfamily 6 (GCNF) · subfamily 0 (DAX1, SHP)(2.2) Other Cys4(2.3) Cys2His2General transcription factors (TFIIA, TFIIB, TFIID, TFIIE (1, 2), TFIIF (1, 2), TFIIH (1, 2, 4, 2I, 3A, 3C1, 3C2))
ATBF1 · BCL (6, 11A, 11B) · CTCF · E4F1 · EGR (1, 2, 3, 4) · ERV3 · GFI1 · GLI-Krüppel family (1, 2, 3, REST, S2, YY1) · HIC (1, 2) · HIVEP (1, 2, 3) · IKZF (1, 2, 3) · ILF (2, 3) · KLF (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17) · MTF1 · MYT1 · OSR1 · PRDM9 · SALL (1, 2, 3, 4) · SP (1, 2, 4, 7, 8) · TSHZ3 · WT1 · Zbtb7 (7A, 7B) · ZBTB (16, 17, 20, 32, 33, 40) · zinc finger (3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 300, 318, 330, 346, 350, 365, 366, 384, 423, 451, 452, 471, 593, 638, 644, 649, 655)(2.4) Cys6(2.5) Alternating composition(3) Helix-turn-helix domains (3.1) HomeodomainARX · CDX (1, 2) · CRX · CUTL1 · DBX (1, 2) · DLX (3, 4, 5) · EMX2 · EN (1, 2) · FHL (1, 2, 3) · HESX1 · HHEX · HLX · Homeobox (A1, A2, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) · HOPX · IRX (1, 2, 3, 4, 5, 6, MKX) · LMX (1A, 1B) · MEIS (1, 2) · MEOX2 · MNX1 · MSX (1, 2) · NANOG · NKX (2-1, 2-2, 2-3, 2-5, 3-1, 3-2, 6-1, 6-2) · NOBOX · PBX (1, 2, 3) · PHF (1, 3, 6, 8, 10, 16, 17, 20, 21A) · PHOX (2A, 2B) · PITX (1, 2, 3) · POU domain (PIT-1, BRN-3: A, B, C, Octamer transcription factor: 1, 2, 3/4, 6, 7, 11) · OTX (1, 2) · PDX1 · SATB2 · SHOX2 · VAX1 · ZEB (1, 2)(3.2) Paired box(3.3) Fork head / winged helix(3.4) Heat Shock Factors(3.5) Tryptophan clusters(3.6) TEA domain(4) β-Scaffold factors with minor groove contacts (4.1) Rel homology region(4.2) STAT(4.3) p53(4.4) MADS box(4.6) TATA binding proteins(4.7) High-mobility group(4.10) Cold-shock domainCSDA, YBX1(4.11) Runt(0) Other transcription factors (0.2) HMGI(Y)(0.3) Pocket domain(0.6) Miscellaneoussee also transcription factor/coregulator deficiencies
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)Categories:- Human proteins
- Chromosome 1 gene stubs
- Intracellular receptors
- Transcription factors
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