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 non-genotoxic stresses such as serum starvation, ultraviolet irradiation and treatment with alkylating agents. Their coordinate induction is a growth arrest signal which may play an important 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-1 cells results in an attenuated induction of the three major gadd transcripts by methyl methanesulfonate (MMS), and almost completely blocks the response to ultraviolet (UV) radiation. Myc acts in part by reducing the stress-responsiveness of the gadd45 promoter, as a c-myc expression vector strongly suppressed activation of gadd45-reporter constructs. This activity of Myc localizes to a recently described GC-rich binding site within the gadd45 promoter. These results indicate that a coordinate down-regulation of the gadd gene response is one mechanism by which Myc can circumvent growth arrest and contribute to the neoplastic phenotype.
Amundson
S A
SA
NCI, NIH, Bethesda, Maryland 20892, USA.
Zhan
Q
Q
Penn
L Z
LZ
Fornace
A J
AJ
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008741:Methyl Methanesulfonate / Q000633:toxicity; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D015854:Up-Regulation; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008741:Methyl Methanesulfonate; D009153:Mutagens; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000097642:GADD45 Proteins; C497251:Ddit3 protein, rat