c-Fos is involved in the cellular defence against the genotoxic effect of UV radiation

Abstract

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.

Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

“…Wt cells were exposed to 0 or 7.5 UV-C in the presence or absence of 1 mM actinomycin D for 3 or 6 h. Total RNA was isolated and RT-PCR was performed using fen1 or, as positive control, gapdh-specific primers To see whether Fen1 is also inducible in other rodent cell lines, we assayed 3T3 and f20 mouse fibroblasts: both are p53 proficient (data not shown). A line isogenic to f20 is f10, which expresses mutated p53 (Haas and Kaina, 1995, and data not shown). In the lines expressing wt p53, Fen1 increased after UV-C light exposure, whereas in f10 cells no increase was observed (Figure 5b,upper panel).…”

“…f10 cells are not only mutated in p53 but also deficient for c-Fos. Previously we reported that c-fos knockout cells (both established and primary fosÀ/À cell lines) are hypersensitive to UV-C light (Haas and Kaina, 1995;Lackinger and Kaina, 2000;Lackinger et al, 2001). Therefore, we were interested to learn whether c-Fos deficiency impacts Fen1 induction.…”

“…fosp53À/ÀBK10 ¼ fosp53À/À, Swiss albino 3T3, f20 and f10) were described previously (Haas and Kaina, 1995;Lackinger and Kaina, 2000;Lackinger et al, 2001). The cells were grown in Dulbecco's minimal essential medium (DMEM) containing 10% fetal bovine serum (FBS), in 7% CO 2 at 371C.…”

ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth

“…Activation of transcription factors by DNA damage directly enhances/represses the transcription of their targeted genes, which can exert biological functions in cellular responses. Several transcription factors, such as p53, c-Myc, AP-1 (c-jun and c-fos) and Oct-1, have been characterized to play important roles in the control of cell cycle checkpoints, apoptosis and signaling transduction pathways (Amundson et al, 1998;Haas and Kaina, 1995;Hollander and Fornace, 1989;Jin et al, 2001;Kastan et al, 1992;Kumari and Alvarez-Gonzalez, 2000;Rupnow et al, 1998;Tong et al, 2001;Yu et al, 2002;Zhan et al, 1994a;Zhao et al, 2000).…”

Effects of Heavy Metals on Mitogen-Activated Protein Kinase Pathways.

“…This suggests that c-fos plays a protective role against the cytotoxic effects of cadmium. Since c-fos-deficient cells were sensitive to hexavalent chromium 43) , UV [44][45][46] , ionizing radiation 46) and DNA-damaging agents 46,47) , c-fos may be involved in cellular protective functions, especially against genotoxic stresses including heavy metals.…”