Carcinogenesis Advance Access published online on July 8, 2006
Carcinogenesis, doi:10.1093/carcin/bgl119
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1 Department of Toxicology, University of Mainz, Germany
* To whom correspondence should be addressed. 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 dimmers (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 Jun 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 up-regulation 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.
Received April 10, 2006
Revised June 14, 2006
Accepted June 20, 2006
CARCINOGENESIS
A role for UV-light induced c-Fos: stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis
Markus Christmann 1,
Maja T. Tomicic 1,
Dorthe Aasland 1,
and
Bernd Kaina 1 *
Bernd Kaina, E-mail: kaina{at}uni-mainz.de
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