title: Inhibition of p27Kip1 gene transcription by mitogens.
abstract: How mitogens reduce the abundance of the cell cycle inhibitor p27(Kip1) is an important question, and regulation of p27(Kip1) translation and turnover has been described. Here we show that platelet-derived growth factor (PDGF) reduces the activity of the p27(Kip1) promoter and the abundance of the p27(Kip1) transcript in density-arrested mouse fibroblasts. Inhibition of p27(Kip1) gene expression by PDGF required protein synthesis and histone deacetylase activity but not Akt or ERK activity. PDGF increased the expression of c-Myc in the absence but not presence of a histone deacetylase inhibitor, and c-Myc inhibited p27(Kip1) promoter activity when ectopically expressed in fibroblasts. c-Myc targeted the same region of the p27(Kip1) promoter as did PDGF (deletion analysis) and interacted with this region in vivo (chromatin immunoprecipitation assay). Collectively, these findings suggest that c-Myc mediates the inhibitory effects of PDGF on the p27(Kip1) promoter. We also demonstrate reductions in p27(Kip1) mRNA abundance in primary splenocytes exposed to concanavalin A and in T cells exposed to interleukin-2 (IL-2). In contrast to PDGF in fibroblasts, IL-2 required Akt activity for maximal reductions in p27(Kip1) promoter activity and mRNA abundance in T cells. Thus, mitogens repress p27(Kip1) gene transcription in multiple systems and by multiple mechanisms.
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Bagui
authors.forename: Dongming
authors.initials: D
authors.lastname: Cui
authors.forename: Sangita
authors.initials: S
authors.lastname: Roy
authors.forename: Subhra
authors.initials: S
authors.lastname: Mohapatra
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Shor
authors.forename: Le
authors.initials: L
authors.lastname: Ma
authors.forename: W Jackson
authors.initials: WJ
authors.lastname: Pledger
mesh_terms: D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D008934:Mitogens / Q000494:pharmacology*; D041681:NIH 3T3 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D006877:Hydroxamic Acids; D008934:Mitogens; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; C012589:trichostatin A; D020929:Mitogen-Activated Protein Kinase Kinases; D006655:Histone Deacetylases