A role for transcriptional repression of p21(CIP1) by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest

c-Myc plays a vital role in cell-cycle progression. Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor β (TGFβ) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-regulation of c-Myc followed by up-regulation of p21(CIP1). A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle block induced by TGFβ treatment. The induction of p21(CIP1) transcription by TGFβ was blocked in human keratinocyte cells stably expressing c-Myc. Furthermore, overexpression of c-Myc in NIH 3T3 cells repressed the basal levels of p21(CIP1) mRNA. Repression of p21(CIP1) transcription by c-Myc occurred at the promoter level in a region near the start site of transcriptional initiation and was independent of histone deacetylase activity. These data suggest that the down-regulation of c-Myc after TGFβ signaling is important for subsequent regulation of p21(CIP1) and cell-cycle inhibition. Thus, repression of the cell-cycle inhibitory gene p21(CIP1) plays a role in c-Myc-dependent cell-cycle progression.