Protein kinase C δ regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage

The p53 tumor suppressor is activated in the cellular response to genotoxic stress. Transactivation of p53 target genes dictates cell cycle arrest and DNA repair or induction of apoptosis; however, a molecular mechanism responsible for these distinct functions remains unclear. Recent studies revealed that phosphorylation of p53 on Ser(46) was associated with induction of p53AIP1 expression, resulting in the commitment of the cell fate into apoptotic cell death. Moreover, upon exposure to genotoxic stress, p53DINP1 was expressed and recruited a kinase(s) to p53 that specifically phosphorylated Ser46. Here, we show that the pro-apoptotic kinase, protein kinase C delta(PKC delta), is involved in phosphorylation of p53 on Ser46. PKC delta-mediated phosphorylation is required for the interaction of PKC delta with p53. The results also demonstrate that p53DINP1 associates with PKC delta upon exposure to genotoxic agents. Consistent with these results, PKC delta potentiates p53-dependent apoptosis by Ser46 phosphorylation in response to genotoxic stress. These findings indicate that PKC delta regulates p53 to induce apoptotic cell death in the cellular response to DNA damage.