Constitutive androstane receptor

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Nuclear receptor subfamily 1, group I, member 3
Protein NR1I3 PDB 1xv9.png
PDB rendering based on 1xv9.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NR1I3 ; CAR; CAR1; MB67
External IDs OMIM603881 MGI1346307 HomoloGene3759 IUPHAR: NR1I3 ChEMBL: 5503 GeneCards: NR1I3 Gene
RNA expression pattern
PBB GE NR1I3 207007 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 9970 12355
Ensembl ENSG00000143257 ENSMUSG00000005677
UniProt Q14994 O35627
RefSeq (mRNA) NM_001077469 NM_001243062
RefSeq (protein) NP_001070937 NP_001229991
Location (UCSC) Chr 1:
161.2 – 161.21 Mb
Chr 1:
171.21 – 171.22 Mb
PubMed search [1] [2]

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 pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated.[2] Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.

Function[edit]

CAR is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand and is regulated by both agonists and inverse agonists. Ligand binding results in translocation of CAR from the cytosol into the nucleus, where the protein can bind to specific DNA sites, called response elements. Binding occurs both as a monomer and together with the retinoid X receptor (RXR) resulting in activation or repression of target gene transcription. CAR-regulated genes are involved in drug metabolism and bilirubin clearance. Examples for CAR-regulated genes are members of the CYP2B, CYP2C, and CYP3A subfamilies, sulfotransferases, and glutathione-S-transferases.[3] Ligands binding to CAR include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. [4]

Activation mechanism[edit]

Phosphorylated CAR is forming a multiprotein complex with the heat shock protein 90 (hsp90) and the cytoplasmic CAR retention protein (CCRP) which keep CAR in the cytosol thereby inactivating it. [5] CAR can be activated in two ways: by direct binding of a ligand (e.g. TCPOBOP) or indirect regulation by phenobarbital (PB), a common seizure medication, facilitating the dephosphorylation of CAR through protein phosphatase 2 (PP2A) (Fig. 1). Both lead to the release of CAR from the multiprotein complex and its translocation into the nucleus. Here, CAR forms a heterodimer with retinoid X receptor (RXR) and interacts with the phenobarbital-responsive enhancer module (PBREM), a distal enhancer activating transcription of CAR target genes. [6]

The consensus sequence of PBREM, containing direct repeat-4 motifs, was found to be conserved in mouse, rat and human 'Cyp2b' genes.[7][8][9]

Direct activation by TCPOBOP[edit]

1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) is thought bind directly to CAR, thus inducing its translocation into the nucleus.[10]

Indirect activation by PB[edit]

Phenobarbital, a widely used anticonvulsant, is used as a model ligand for indirect CAR activation. Some findings[11]

[12] suggest that PB activates CAR, by inducing the dephosphorylation of CAR through PP2A. How PP2A is activated remains unclear, but different mechanisms have been described.

The recruitment of PP2A has been shown to be mediated by the multiprotein complex.8 As PB is involved in the activation of AMP-activated protein kinase, it has been suggested that AMPK activates PP2A.[13]

Alternatively, PP2A might be activated through another pathway including the epidermal growth factor receptor (EGFR) and the receptor for activated C kinase 1 (RACK1). In the absence of PB, the epidermal growth factor (EGF) binds to EGFR, thereby activating the steroid receptor coactivator-1 (Src1), which in turn phosphorylates RACK1. Upon PB-exposure, PB binds competitively to EGFR and thus leads to inactivation of Src1. This results in a dephosphorylation of RACK1, which can subsequently stimulate PP2A to activate CAR. [12]

Figure 1 - Activation mechanisms of CAR: Inactivated CAR is retained in the cytosol. Upon binding of TCPOBOP, CAR gets dephosphorylated by PP2A and translocates into the nucleus. Here, it forms a complex with RXR and binds to the PB-responsive enhancer module. Another possibility to activate CAR is the indirect activation through PB. PB binds competitively to EGFR, thus inducing the dephosphorylation of RACK-1. RACK-1 then stimulates PP2A to dephosphorylate CAR, which is then translocated into the nucleus.

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, Lehmann JM, Negishi M (2002). "Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital". Mol. Pharmacol. 61 (1): 1–6. PMID 11752199. 
  4. ^ "Entrez Gene: NR1I3 nuclear receptor subfamily 1, group I, member 3". 
  5. ^ Kodama S, Negishi M; Negishi, M. (2006). "Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car.". Drug Metab. Rev. 38: 75–87. doi:10.1080/03602530600569851. PMID 16684649. 
  6. ^ Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M (1999). "Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene". Mol. Cell. Biol. 19 (9): 6318–22. PMC 84602. PMID 10454578. 
  7. ^ Honkakoski P, Moore R, Washburn KA, Negishi M (1998). "Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene". Mol. Pharmacol. 53 (4): 597–601. doi:10.1124/mol.53.4.597. PMID 9547348. 
  8. ^ Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M (1999). "The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene". J. Biol. Chem. 274 (10): 6043–6. doi:10.1074/jbc.274.10.6043. PMID 10037683. 
  9. ^ Mäkinen J, Frank C, Jyrkkärinne J, Gynther J, Carlberg C, Honkakoski P (August 2002). "Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors". Mol. Pharmacol. 62 (2): 366–78. doi:10.1074/jbc.274.10.6043. PMID 12130690. 
  10. ^ Tzameli I, Pissios P, Schuetz EG, Moore DD (May 2000). "The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR". Mol. Cell. Biol. 20 (9): 2951–8. doi:10.1128/MCB.20.9.2951-2958.2000. PMC 85552. PMID 10757780. 
  11. ^ Yoshinari K, Kobayashi K, Moore R, Kawamoto T, Negishi M (July 2003). "Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital". FEBS Lett. 548 (1-3): 17–20. PMID 12885400. 
  12. ^ a b Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, Negishi M (2013). "Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling.". Sci. Signal. 6: ra31. doi:10.1126/scisignal.2003705. PMID 23652203. 
  13. ^ Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, Wolf CR (2005). "AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line.". J. Biol. Chem. 280: 4367–4373. doi:10.1074/jbc.M412711200. PMID 15572372. 

Further reading[edit]

  • Masuno M, Shimozawa N, Suzuki Y, Kondo N, Orii T, Tsukamoto T, Osumi T, Fujiki Y, Imaizumi K, Kuroki Y (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, Simha D, Lee YK, Seol W, Moore DD (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, Chen J, Simha D, Seol W, Evans RM, Moore DD (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, Petz L, Kemper JK (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, Robertson GR, Liddle C (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, Wei P, Moore DD (2002). "Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR". Science 298 (5592): 422–4. doi:10.1126/science.1073502. PMID 12376703. 
  • 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, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT (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, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, Evans RM (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. 
  • Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD (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. 
  • Auerbach SS, Ramsden R, Stoner MA, Verlinde C, Hassett C, Omiecinski CJ (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. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.