Carcinogenesis Advance Access originally published online on July 8, 2006
Carcinogenesis 2007 28(1):183-190; doi:10.1093/carcin/bgl119
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A role for UV-light-induced c-Fos: stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis
Department of Toxicology, University of Mainz Germany
*To whom correspondence should be addressed at: Department of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. Tel: ++49 6131 393 3246; Fax: ++49 6131 393 3421; Email: kaina{at}uni-mainz.de
UV light (UV-C) is a potent inducer of the c-fos gene. Cells lacking c-Fos are hypersensitive to the cytotoxic effect of UV-C indicating a protective role of c-fos induction. Here we show that cells deficient in c-Fos (fos–/–) are unable to remove cyclobutane pyrimidine dimers (CPDs) from DNA and undergo apoptosis at high frequency via the Fas pathway. We also show that in c-Fos-deficient cells the activation of c-Jun N-terminal kinase (JNK) by UV-C differs from the wild-type (wt, fos+/+). In wt cells JNK activation is transient, returning to control level 5–8 h after treatment, whereas in c-Fos-deficient cells JNK activation was long-lasting and did not return to control level. Inhibition of early JNK activation by the JNK inhibitor SP600125 attenuated CPD repair and increased UV-C induced apoptosis whereas inhibition of late JNK activation attenuated the apoptotic response of c-Fos-deficient cells. Late and sustained activation of JNK resulted in upregulation of fas (CD95, apo-1) ligand and induction of caspase 8-dependent apoptosis. The data indicate that the immediate-early induction of the JNK/c-fos pathway stimulates the repair of UV-C induced DNA lesions that protects against apoptosis. If this does not occur, cells do not recover from transcription blockage leading, as shown for c-Fos-deficient cells, to a reduced expression of MKP1, sustained JNK activation and fasL overexpression that finally results in activation of the death receptor pathway. The data support the hypothesis that non-repaired DNA damage is the cause for the late and sustained activation of the MAP kinase pathway in response to genotoxins.
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