ATM/ATR ACTIVATION IS INVOLVED IN p19INK4d INDUCTION IN RESPONSE TO DNA DAMAGE BY MULTIPLE GENOTOXICS

MARÍA FLORENCIA OGARA; JULIETA M. CERUTI; MARÍA E. SCASSA; EDUARDO T. CÁNEPA

Pinamar, Argentina.

Congreso; XLI Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2005

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

p19INK4d is a member of INK4, a family of proteins involved in cell cycle regulation causing CDK4/6 inhibition. Recently, this protein has been implicated in the cellular response evoked by UV-damaged DNA. The aim was to investigate the role of p19 in DNA damage response and to characterize the signal transduction pathways involved. SH-SY5Y neuroblastoma cells treated with the antitumoral drug cisplatin or b-amyloid peptide cause a doses-dependent increase of p19 mRNA levels, as determined by Northern blot. p19-overexpressing cells treated with any of the aforementioned genotoxics displayed an enhanced DNA repair and were more resistant to apoptosis, as determined by unscheduled DNA synthesis and caspase-3 activity assays, respectively. Opposite effects were observed in p19-deficient cells. In WI38 human fibroblasts 5 mM caffeine, an ATM/ATR inhibitor, blocked cisplatin-mediated p19 induction, although the basal expression remained unaltered. Immunoprecipitation assays demonstrated that p19 was not only induced but phosphorylated in response to cisplatin. The present results confirm a role of p19 in the response to DNA damage caused by several genotoxics and suggest the involvement of PI3 kinase-like proteins, ATM/ATR, in p19 induction/activation.