P4-321: Pro-apoptotic function of Pin1-mediated notch activation

The peptidyl-prolyl cis/trans isomerase (PPIase) Pin1 regulates factors involved in the control of cell growth and apoptosis. Notch1 is a transmembrane receptor crucial for neuronal development, neurogenesis, and neuronal death. Proteolytic cleavage of Notch1 by γ-secretase results in liberation of the intracellular domain of Notch1 (NICD), which translocates into the nucleus and regulates gene expression. Glucose Deprivation Western blot Analysis Cell culture and transfection Here, we demonstrate that Pin1 stimulates Notch1 activation leading to an increased production of Notch1 intracellular domain (NICD) by gamma-secretase. Overexpression of Pin1 enhances gamma-secretase activity and NICD production. Conversely, down-regulation of Pin1 using siRNA reduces gamma-secretase activity and NICD production. Pin1 overexpressed cells were vulnerable to glucose deprivation or chemical hypoxia induced cell death. The incidence of glucose deprivation or hypoxia-induced cell death was diminished in Pin1(-/-) mouse embryonic fibroblast cells or neuronal cells transfected with Pin1 siRNA. These results suggest novel functions of Pin1 in Notch1 activation and Notch1-mediated cell death.