A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest.

Claassen GF, Hann SR
Proc Natl Acad Sci U S A. 2000 97 (17): 9498-503

PMID: 10920185 · PMCID: PMC16893 · DOI:10.1073/pnas.150006697

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 beta (TGFbeta) 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 TGFbeta treatment. The induction of p21(CIP1) transcription by TGFbeta 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 TGFbeta 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.

MeSH Terms (23)

3T3 Cells Animals Cell Cycle Cell Line Cyclin-Dependent Kinase Inhibitor p21 Cyclins Down-Regulation Gene Silencing Histone Deacetylase Inhibitors Histone Deacetylases Humans Hydroxamic Acids Mice Promoter Regions, Genetic Proto-Oncogene Proteins c-myc Repressor Proteins Response Elements RNA, Messenger Time Factors Transcription, Genetic Transfection Transforming Growth Factor beta Up-Regulation

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