A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -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 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.
Claassen
G F
GF
Department of Cell Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Hann
S R
SR
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C012589:trichostatin A; D006655:Histone Deacetylases