Jul 11, 2006

A role for UV-light-induced c-Fos: Stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis

Carcinogenesis
Markus ChristmannBernd Kaina

Abstract

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 n...Continue Reading

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Mentioned in this Paper

Biochemical Pathway
c-fos Genes
Apoptosis, Intrinsic Pathway
Mitogen-Activated Protein Kinases
Jun D Proteins
Base Excision Repair
FAS gene
FASLG wt Allele
Reverse Transcriptase Polymerase Chain Reaction
Nucleotide Excision Repair Pathway

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