p19INK4d is a potential neuronal survival factor

OGARA M.F.; CASTILLO D.S.; BERARDINO B.G.; CÁNEPA, E.T.

Puerto Madryn

Congreso; XLVI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN EN BIOQUÍMICA Y BIOLOGÍA MOLECULAR (SAIB); 2010

SOCIEDAD ARGENTINA DE INVESTIGACIÓN EN BIOQUÍMICA Y BIOLOGÍA MOLECULAR (SAIB)

The early and wide expression of p19INK4d in the brain and its rolein DNA repair suggest that it might be involved in protectingneurons from cell death. The aim of this work was to examine therole of p19 in differentiated SH-SY5Y cells and primary cultures ofrat hippocampal neurons subjected to genotoxic agents such as beta-amyloidpeptid (BA) and neocarzinostatin (NCS).BA and NCS induced p19 expression and phosphorylation. Theseeffects were recapitulated by treatment with a Ca2+ ionophore andby increasing the extracellular K+ concentration, suggesting thatthey both involve intracellular Ca2+ mobilization. p19phosphorylation following genotoxic stress was impaired bydownregulation of CDK5 by antisense and reduction of its activitythrough inhibition of calpain, a CDK5 stimulator. This indicatedthat this process is mediated by CDK5. Experiments using E2Fdecoy oligonucleotides and reporter assays showed that E2F1 isresponsible for p19 induction upon DNA damage.p19 overexpression stimulated DNA repair in neuronal cellstreated with BA or NCS, whereas its downregulation had theopposite effect. Consistently, p19 ablation reduced cell viabilityand caused an increase in caspase 3 activity in hippocampalneurons following genotoxic stress.These results support a role for p19 as a survival factor that protectsneurons from apoptosis induced by genotoxic agents.