6533b871fe1ef96bd12d22a7

RESEARCH PRODUCT

Inducible Responses and Protective Functions of Mammalian Cells Upon Exposure to UV Light and Ionizing Radiation

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In mammalian cells, ultraviolet (UV) light as well as ionizing radiation (IR) transcriptionally activate the early-responsive genes c-fos, c jun,junB and junD. The induction of fos and jun by UV-C is currently understood to occur via activation of the EGF receptor and the Ras, Raf, ERK and JNK cascade leading ultimately to phosphorylation of transcription factors such as Fos and Jun (AP-1). This, finally, gives rise to transcriptional activation of AP-1 dependent target genes. Another gene we have recently demonstrated to be immediate-early inducible upon UV-irradiation encodes the Ras-related small GTPase RhoB. The pathway of rhoB induction appears to be different from fos/jun because (i) rhoB does not respond to treatment with TPA and (ii) UV stimulation of rhoB appears to be independent of ERK and JNK. The physiological function of RhoB is still poorly understood. Whether genes involved in cellular defense against UV-C and IR are targeted by Fos/Jun is an intriguing question. The fact that Fos/Jun are induced by genotoxic exposures indicates that this very early genotoxic response plays a physiological role in cellular defense against induced DNA damage. We have experimentally addressed this by utilizing cells for genotoxicity studies which are unable to induce c-Fos because of homozygous mutation of the gene. c-Fos deficient cells were shown to be hypersensitive to the cytotoxic effect (both necrotic and apoptotic death) of UV-C. Also, they responded with a markedly elevated level of UV-induced chromosomal aberrations. The extent of overall DNA repair synthesis was not significantly reduced, indicating that DNA repair deficiency is not the cause of the UV hypersensitivity observed. Interstingly, c-Fos deficient cells were cross-sensitive to a variety of chemical DNA damaging agents, but not to IR. The recovery from UV and chemical agent-induced immediate block to DNA replication was impaired in c-Fos deficient cells. From this we hypothesized that induction of Fos/Jun is required to activate gene(s) the products of which are involved in abolition of replication blockage upon the induction of DNA damage. Induction of Fos/Jun as well as p53 may also be directly involved in regulation of DNA repair genes, such as 06-methylguanine-DNA methyltransferase which is inducible upon genotoxic treatment. Another gene induced especially by oxidative stress is apurinic endonuclease which appears to be involved in adaptive response. Overexpression of RhoB in NIH3T3 cells gives rise to an altered survival response upon genotoxic exposure indicating this inducible function also to play a role in cellular defense.