Transient excess of MYC activity can elicit genomic instability and tumorigenesis.
Overexpression of the MYC protooncogene has been implicated in the genesis of diverse human tumors. Tumorigenesis induced by MYC has been attributed to sustained effects on proliferation and differentiation. Here we report that MYC may also contribute to tumorigenesis by destabilizing the cellular genome. A transient excess of MYC activity increased tumorigenicity of Rat1A cells by at least 50-fold. The increase persisted for >30 days after the return of MYC activity to normal levels. The brief surfeit of MYC activity was accompanied by evidence of genomic instability, including karyotypic abnormalities, gene amplification, and hypersensitivity to DNA-damaging agents. MYC also induced genomic destabilization in normal human fibroblasts, although these cells did not become tumorigenic. Stimulation of Rat1A cells with MYC accelerated their passage through G1/S. Moreover, MYC could force normal human fibroblasts to transit G1 and S after treatment with N-(phosphonoacetyl)-L-aspartate (PALA) at concentrations that normally lead to arrest in S phase by checkpoint mechanisms. Instead, the cells subsequently appeared to arrest in G2. We suggest that the accelerated passage through G1 was mutagenic but that the effect of MYC permitted a checkpoint response only after G2 had been reached. Thus, MYC may contribute to tumorigenesis through a dominant mutator effect.
Felsher
D W
DW
Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco 94143-1270, USA. felsher@itsa.ucsf.edu
Bishop
J M
JM
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002999:Clone Cells; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016259:Genes, myc; D006801:Humans; D007231:Infant, Newborn; D007621:Karyotyping; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous