Role of p160 coactivator complex in the activation of liver X receptor.
OBJECTIVE
Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer.


RESULTS
Overexpression of LXRalpha, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner.


CONCLUSIONS
The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.
Huuskonen
Jarkko
J
Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0130, USA. jhuu6676@itsa.ucsf.edu
Fielding
Phoebe E
PE
Fielding
Christopher J
CJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000123:Acetyltransferases / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins; D019281:Dimerization; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007668:Kidney; D000071518:Liver X Receptors; D046911:Macromolecular Substances; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000502:physiology*; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D057093:Orphan Nuclear Receptors; D011484:Protein-Arginine N-Methyltransferases; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C577836:ABCA1 protein, human; C498001:NCOA2 protein, human; C000605213:NR1H3 protein, human; C003585:22-hydroxycholesterol; C119966:coactivator-associated arginine methyltransferase 1; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human