CELL CYCLE INHIBITOR, p19INK4d, AS A POTENTIAL NEURONAL SURVIVAL FACTOR

OGARA MF; CASTILLO DS; BERARDINO BG; CÁNEPA ET

Puerto Madryn, Chubut

Congreso; XLVI Reunión anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2010

SAIB

The early and wide expression of p19INK4d in the brain and its role in DNA repair suggest that it might be involved in protecting neurons from cell death. The aim of this work was to examine the role of p19 in differentiated SH-SY5Y cells and primary cultures of rat hippocampal neurons subjected to genotoxic agents such as B-amyloid peptid (BA) and neocarzinostatin (NCS). BA and NCS induced p19 expression and phosphorylation. These effects were recapitulated by treatment with a Ca2+ ionophore and by increasing the extracellular K+ concentration, suggesting that they both involve intracellular Ca2+ mobilization. p19 phosphorylation following genotoxic stress was impaired by downregulation of CDK5 by antisense and reduction of its activity through inhibition of calpain, a CDK5 stimulator. This indicated that this process is mediated by CDK5. Experiments using E2F decoy oligonucleotides and reporter assays showed that E2F1 is responsible for p19 induction upon DNA damage. p19 overexpression stimulated DNA repair in neuronal cells treated with BA or NCS, whereas its downregulation had the opposite effect. Consistently, p19 ablation reduced cell viability and caused an increase in caspase 3 activity in hippocampal neurons following genotoxic stress. These results support a role for p19 as a survival factor that protects neurons from apoptosis induced by genotoxic agents.