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, M yc prevents growth arrest and drives cell cycle progression through th e transcriptional regulation of Myc-target genes. Expression of the gr owth arrest and DNA damage inducible gene 45 (gadd45) is elevated in r esponse to DNA damaging agents, such as ionizing radiation via a p53-d ependent mechanism, upon nutrient deprivation, or during differentiati on. Gadd35 holds a vital role in growth arrest as ectopic expression c onfers a strong block to proliferation. Exposure of quiescent cells to mitogen stimulates a rapid increase in c-Myc expression which is foll owed by the subsequent reduction in gadd45 expression. The kinetics of these two regulatory events suggest that Myc suppresses the expressio n of gadd45, contributing to G0/G1 phase exit of the cell cycle. Indee d, ectopic Myc expression in primary and immortalized fibroblasts resu lts in the suppression of gadd45 mRNA levels, by a mechanism which is independent of cell cycle progression. Using an inducible MycER(TM) sy stem, rapid suppression of gadd45 mRNA is first evident approximately 0.5 h following Myc activation. The reduction in gadd45 mRNA. expressi on occurs at the transcriptional level and is mediated by a p53-indepe ndent pathway. Moreover, Myc suppression and p53 induction of gadd45 f ollowing exposure to ionizing radiation are noncompetitive co-regulato ry events. Myc suppression of gadd45 defines a novel pathway through w hich Myc promotes cell cycle entry and prevents growth arrest of trans formed cells.