Three Distinct Signalling Responses by Murine Fibroblasts to Genotoxic Stress

Genotoxic stress triggers signalling pathways that mediate either the protection or killing of affected cells. Whereas induction of p53 involves events in the cell nucleus, the activation of transcription factors AP-1 and NF-kappaB by ultraviolet radiation is mediated through membrane-associated signalling proteins, ruling out a nuclear signal. An early event in AP-1 induction by ultraviolet radiation is activation of Jun kinases (JNKs), which mediate the induction of the immediate-early genes c-jun and c-fos. The JNKs have also been proposed to mediate the apoptopic response to genotoxins. The non-receptor tyrosine kinase c-Abl is also activated by genotoxic stress. To understand the relationship between these events, we compared the activation of p53, JNK and c-Abl by several DNA-damaging agents in murine fibroblasts. We found that whereas p53 was induced by every genotoxic stimulus tested, c-Abl was activated by most stimuli except ultraviolet irradiation and JNK was strongly stimulated only by ultraviolet light and the alkylating agent methyl methanesulphonate. Activation of JNK by this alkylating agent was normal in c-Abl-null cells but was reduced in c-Src-null cells. Unlike p53 induction, c-Abl activation occurs in the S phase of the cell cycle and does not affect cell proliferation. These findings show that signals generated by genotoxins are transduced by multiple, independent pathways. Only p53 appears to be a universal sensor of genotoxic stress.