p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism.
Transcription of the human caveolin gene, directed by a TATA-less promoter, is downregulated in actively dividing cells during S-phase, together with free cholesterol (FC) efflux. It is upregulated by medium low density lipoprotein FC levels in quiescent cells. In this study, a common mechanism has been identified to coordinate the growth- and FC-dependent expression of caveolin. In human skin fibroblasts, transcription factors E2F/DP-1 and Sp1 bound to adjacent consensus sites at -151 to -138 bp of the caveolin promoter DNA sequence in a complex stabilized by tumor suppressor protein p53. Wild-type p53 also bound directly to DNA to a caveolin promoter sequence containing two consensus half-sites (-292 to -283 bp and -273 to -264 bp) for this transcription factor. SREBP-1, previously identified as a transcriptional regulator of caveolin expression in response to FC, mediated its effect via the same E2F/Sp1 site. Overexpression of E2F or p53 increased E2F binding to the -148 to -141 bp site, increased FC efflux, and inhibited cell division. The mutant protein p53(143V-->A) was inactive. Okadaic acid, previously shown to inhibit growth, FC efflux, and caveolin expression, inhibited E2F/Sp1 binding, while higher concentrations of extracellular FC increased it. The present findings provide a molecular link between the cell cycle and FC homeostatic effects of caveolin. These results also describe a novel mechanism of action for p53 in a TATA-less gene promoter and provide further evidence for a significant regulatory role for FC in cell cycle progression.
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Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, California 94143, USA.
Fielding
C J
CJ
Fielding
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PE
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D051242:Caveolin 1; D022461:Caveolins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011479:Protamines / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D016385:TATA Box; D013997:Time Factors; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
C495540:CAV1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D051242:Caveolin 1; D022461:Caveolins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011479:Protamines; D056465:Retinoblastoma-Binding Protein 1; C497387:SREBF1 protein, human; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D002784:Cholesterol; D008156:Luciferases