Haas S, Kaina B
Institute of Toxicology, University of Mainz, Germany.
Carcinogenesis. 1995 May;16(5):985-91. doi: 10.1093/carcin/16.5.985.
The proto-oncogene c-fos encodes a nuclear protein that forms together with c-Jun or other members of the Jun family the transcription factor AP-1. The c-fos gene is inducible by UV radiation and other DNA damaging treatments which may indicate that it is required in defence against DNA damaging agents. To address this hypothesized function of c-Fos, we have compared the response of mouse fibroblasts deficient in c-Fos with the corresponding wild-type cells towards the genotoxicity of UV radiation. It is shown here that lack of c-Fos renders cells hypersensitive to the cytotoxic effect of UV light and gives rise to significant increases of UV-induced chromosomal mutations and DNA breakage. Cells lacking c-Fos were basically able to perform UV-induced repair replication, as measured by unscheduled DNA synthesis. However, with high doses of UV c-Fos deficient cells proved to be less efficient in repair synthesis than wild-type cells. Measurement of overall DNA synthesis after UV irradiation revealed that cells deficient in c-Fos are more inhibited in their recovery from the UV-induced block to replication. These data strongly suggest that c-Fos is involved in regulating the timing of DNA replication after UV irradiation by abolition of the UV-induced block to replication and thus appears to play a decisive role in the cellular defence against the genotoxic effects induced by UV radiation.
原癌基因c-fos编码一种核蛋白，该蛋白与c-Jun或Jun家族的其他成员共同形成转录因子AP-1。c-fos基因可被紫外线辐射和其他DNA损伤处理诱导，这可能表明它在抵御DNA损伤剂方面是必需的。为了探究c-Fos的这一假定功能，我们比较了缺乏c-Fos的小鼠成纤维细胞与相应野生型细胞对紫外线辐射遗传毒性的反应。本文结果表明，缺乏c-Fos会使细胞对紫外线的细胞毒性作用高度敏感，并导致紫外线诱导的染色体突变和DNA断裂显著增加。通过非定规DNA合成测定，缺乏c-Fos的细胞基本能够进行紫外线诱导的修复复制。然而，在高剂量紫外线照射下，缺乏c-Fos的细胞在修复合成方面比野生型细胞效率更低。紫外线照射后总体DNA合成的测定表明，缺乏c-Fos的细胞从紫外线诱导的复制阻滞中恢复的能力受到更大抑制。这些数据强烈表明，c-Fos通过消除紫外线诱导的复制阻滞参与调节紫外线照射后DNA复制的时间，因此似乎在细胞抵御紫外线辐射诱导的遗传毒性作用中起决定性作用。
