Finkel-Biskis-Reilly mouse osteosarcoma virus v-fos inhibits the cellular response to ionizing radiation in a myristoylation-dependent manner.
DNA damage is recognized as a central component of carcinogenesis. DNA-damaging agents activate a number of signal transduction pathways that lead to repair of the DNA, apoptosis, or cell cycle arrest. It is reasoned that a cell deficient in DNA repair is more likely to acquire other cancer-promoting mutations. Despite the recent interest in the link between DNA damage and carcinogenesis, retroviral oncogenes have not yet been shown to affect the DNA damage-signaling pathway. In this report, we show that Finkel-Biskis-Reilly mouse osteosarcoma virus (FBR) v-fos, the retroviral homologue of the c-fos proto-oncogene, inhibits the cellular response to ionizing radiation. Cells that express FBR v-Fos show a decreased ability to repair DNA damage caused by ionizing radiation, and these cells show decreased survival in response to ionizing radiation. In addition, FBR v-Fos inhibits DNA-dependent protein kinase, a kinase specifically activated upon exposure to ionizing radiation. These effects were specific to ionizing radiation, as no effect of FBR v-Fos on the UV light signaling pathway was seen. Last, these effects were dependent on a lipid modification required for FBR v-Fos tumorigenesis, that of myristoylation of FBR v-Fos. A non-myristoylated mutant FBR v-Fos caused none of these effects. This study suggests that a retroviral oncogene can lead to an increased genomic instability, which can ultimately increase the carcinogenic potential of a cell.
Abbott
D W
DW
Departments of Cell Biology, Pathology and Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Holt
J T
JT
D000818:Animals; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016761:Oncogene Proteins v-fos / Q000235:genetics*; D000090063:Proto-Oncogene Mas
C000715470:MAS1 protein, human; D016761:Oncogene Proteins v-fos; D000090063:Proto-Oncogene Mas