MYC SUPPRESSES INDUCTION OF THE GROWTH ARREST GENES GADD34, GADD45, AND GADD153 BY DNA-DAMAGING AGENTS

The growth arrest and DNA damage inducible (gadd) genes are induced by various genotoxic and nongenotoxic stresses such as serum starvation, ultraviolet irradiation and treatment with alkylating agents. Their c oordinate induction is a growth arrest signal which may play an import ant role in the response of cells to DNA damage. Conversely, c-myc is a strong proliferative signal, and overexpression of Myc is frequently observed in cancer cells, We have found that ectopic expression of v- myc in RAT-I cells results in an attenuated induction of the three maj or gadd transcripts by methyl methanesulfonate (MMS), and almost compl etely blocks the response to ultraviolet (UV) radiation. Myc acts in p art by reducing the stress-responsiveness of the gadd45 promoter, as a c-myc expression vector strongly suppressed activation of gadd-report er constructs. This activity of Myc localizes to a recently described CC-rich binding site within the gadd45 promoter. These results indicat e that a coordinate down-regulation of the gadd gene response is one m echanism by which Myc can circumvent growth arrest and contribute to t he neoplastic phenotype.