Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 75
c-Jun as a sensor of DNA damage
Vinciguerra M.1-2, Esposito I.2, Cosentino C.2, Maggiolini M.1 and Musti A.M.1-2
1. Dipart. Farmaco-Biologico Università della Calabria, Rende, Italy
2. Dipart. Biol. Patol. Cell. Mol. I Università di Napoli “Federico II”, Italy
DNA damage elicits a cellular response resulting in the onset of cell cycle delay, DNA repair
or apoptosis. Central to this process is the DNA-damage dependent activation of three IP3
kinase family members ATM, ATR and DNA-PK, which in turn initiate phosphorylation of
proteins involved in the DNA damage pathway. The inability to respond properly to DNA
damage leads to genetic instability, which in turn may enhance the rate of cancer
development. Emerging evidence suggest that, in early stages of oncogenesis, the surviving
transformed cells can be reprogrammed to cell death trough the stress signalling activated by
DNA-damaging anticancer chemotherapies. However advance tumors are frequently resistant
to these treatments, a response that in certain cancer cells seems to be mediated by DNA-PK
over-activity, or by active c-Jun/AP1 transcription factor. c-Jun represents the intersection of
multiple pathways eliciting quite opposite programs, as cellular survival or apoptosis. So far
the regulatory signals leading to this divergence have not been identified. We have
characterized a novel c-Jun consensus phosphorylation site for ATM/ATR kinases. Our
results indicate that DNA-damage dependent phosphorylation of c-Jun at the ATM/ATR
consensus site in turn switches on c-Jun pro-apoptotic phosphorylation at JNK-specific sites.
Furthermore, our results suggest that differential regulation of c-Jun phosphorylation by
apical DNA-sensor kinases may play an important role in the chemoresponsiveness of tumor
cells exposed to DNA-damaging agents such as the topoisomerase
II inhibitor etoposide.
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