Direct control of caveolin-1 expression by FOXO transcription factors.
Protein kinase B can phoshorylate and thereby inactivate the FOXO (forkhead box O) family of transcription factors. When active, FOXO factors can bind to DNA in promoter sequences and subsequently regulate gene expression. We have used DNA microarray analysis to identify potential gene targets of FOXO. In the present study we demonstrate that caveolin-1 is directly controlled by FOXO. Firstly, caveolin-1 expression was increased upon induction or over-expression of FOXO factors at both mRNA and protein levels. Second, we show that endogenous regulation of FOXO activity regulates caveolin-1 levels and that this can be inhibited by dominant-negative FOXO. Third, FOXO activates transcription from the caveolin-1 promoter, and using chromatin immunoprecipitations we demonstrated that this activation occurs via direct interaction of FOXO with the promoter. Finally, we demonstrate FOXO-mediated attenuation of EGF (epidermal growth factor)-induced signalling, which in part is mediated by caveolin-1 expression, as suggested by previous studies [Park, Park, Cho, Kim, Ko, Seo and Park (2000) J. Biol. Chem. 275, 20847-20852]. These findings suggest a novel mechanism by which FOXO factors can exert their cellular effects via transcriptional activation of caveolin-1.
Laboratory of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
A Pieter J
AP
van den Heuvel
Almut
A
Schulze
Boudewijn M T
BM
Burgering
D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases