PI3-kinase/Akt Pathway Mediates Expression of p53 after UVB Irradiation

Abstract

The cells having unrepaired DNA damage after ultraviolet (UV) exposure must go to apoptotic cell death to avoid mutation and transformation leading to cancer, whereas they must be protected against excess apoptotic cell death. The phosphatidylinositol 3-kinase (PI3-kinase)/Akt is a well-known survival pathway which suppresses apoptosis. The p53 tumor suppressor is a universal sensor of genotoxic stress that also regulates apoptosis. Until now, there are many reports of p53 expression after UV irradiation; however, the detailed time-course study has not been performed, especially the relationship with PI3-kinase/Akt pathway. In this study, PI3-kinase/Akt pathway-mediated time-dependent expressions of p53 and its related molecules after UVB irradiation were examined involving induction of apoptosis. Inhibition of PI3-kinase/Akt pathway by wortmannin and siRNA for Akt1 augmented apoptosis induced by UVB irradiation. p53 was time-dependently phosphorylated and stabilized after UVB irradiation, consistent with the expression of p21. Inhibition of PI3-kinase/Akt pathway clearly suppressed the expressions of p53 and p21. On the other hand, the expression levels of p53 in the presence of proteasome inhibitor were same, whether PI3-kinase/Akt pathway was inhibited or not, indicating that the activation of PI3-kinase/Akt pathway after UVB exposure suppressed proteasome-dependent degradation of p53. These results suggested that PI3-kinase/Akt pathway has important roles to mediate p53 expression and induction of apoptosis after UVB irradiation although the p53 revealed no positive correlation with the induction of apoptosis.