Inhibition of p27Kip1 gene transcription by mitogens

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.