ATM/ATR activation is involved in p19INK4d induction in response to DNA damage by multiple genotoxics

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

Pinamar, Provincia de Buenos Aires, 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 (SAIB)

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 the DNA damage response and the signal transduction pathways involved. SHSY-5Y neuroblastoma cells treated with the antitumoral drug cisplatin or the beta-amyloid peptide cause a doses-dependent increase of p19 mRNA, as determined by Northern blot. Run on assay indicates that this effect is exerted at transcriptional level. p19-overexpressing cells treated with any of the above genotoxics were found to increase DNA repair and to be more resistant to apoptosis, as was determined by unscheduled DNA synthesis assay and caspase-3 activity, respectively. Opposite effects were observed in p19-deficient cells. Cisplatin-mediated p19 induction, in WI38 human fibroblasts, was blocked by caffeine, an ATM/ATR inhibitor, although the basal expression was not modified. 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.