p73β is regulated by protein kinase Cδ catalytic fragment generated in the apoptotic response to DNA damage

Abstract

Protein kinase C (PKC) δ is cleaved by caspase-3 to a kinase-active catalytic fragment (PKCδCF) in the apoptotic response of cells to DNA damage. Expression of PKCδCF contributes to the induction of apoptosis by mechanisms that are presently unknown. Here we demonstrate that PKCδCF associates with p73β, a structural and functional homologue of the p53 tumor suppressor. The results show that PKCδCF phosphorylates the p73β transactivation and DNA-binding domains. One PKCδCF-phosphorylation site has been mapped to Ser-289 in the p73β DNA-binding domain. PKCδCF-mediated phosphorylation of p73β is associated with accumulation of p73β and induction of p73β-mediated transactivation. By contrast, PKCδCF-induced activation of p73β is attenuated by mutating Ser-289 to Ala (S289A). The results also demonstrate that PKCδCF stimulates p73β-mediated apoptosis and that this response is attenuated with the p73β(S289A) mutant. These findings demonstrate that cleavage of PKCδ to PKCδCF induces apoptosis by a mechanism in part dependent on PKCδCF-mediated phosphorylation of the p73β Ser-289 site.