Myc represses the growth arrest gene gadd45.
The c-Myc protein strongly stimulates cellular proliferation, inducing cells to exit G0/G1 and enter the cell cycle. At a molecular level, Myc prevents growth arrest and drives cell cycle progression through the transcriptional regulation of Myc-target genes. Expression of the growth arrest and DNA damage inducible gene 45 (gadd45) is elevated in response to DNA damaging agents, such as ionizing radiation via a p53-dependent mechanism, upon nutrient deprivation, or during differentiation. Gadd45 holds a vital role in growth arrest as ectopic expression confers a strong block to proliferation. Exposure of quiescent cells to mitogen stimulates a rapid increase in c-Myc expression which is followed by the subsequent reduction in gadd45 expression. The kinetics of these two regulatory events suggest that Myc suppresses the expression of gadd45, contributing to G0/G1 phase exit of the cell cycle. Indeed, ectopic Myc expression in primary and immortalized fibroblasts results in the suppression of gadd45 mRNA levels, by a mechanism which is independent of cell cycle progression. Using an inducible MycER system, rapid suppression of gadd45 mRNA is first evident approximately 0.5 h following Myc activation. The reduction in gadd45 mRNA expression occurs at the transcriptional level and is mediated by a p53-independent pathway. Moreover, Myc suppression and p53 induction of gadd45 following exposure to ionizing radiation are non-competitive co-regulatory events. Myc suppression of gadd45 defines a novel pathway through which Myc promotes cell cycle entry and prevents growth arrest of transformed cells.
Marhin
W W
WW
Department of Molecular and Medical Genetics, University of Toronto, Ontario Cancer Institute, Canada.
Chen
S
S
Facchini
L M
LM
Fornace
A J
AJ
Penn
L Z
LZ
D000818:Animals; D001665:Binding Sites; D001769:Blood; D002478:Cells, Cultured; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins