INACTIVATION OF DNA-DEPENDENT PROTEIN-KINASE BY PROTEIN-KINASE C-DELTA - IMPLICATIONS FOR APOPTOSIS

Protein kinase CS (PKC delta) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents, tumor necro sis factor, and anti-Pas antibody. A role for PKC delta in apoptosis i s supported by the finding that overexpression of the catalytic fragme nt of PKC delta (PKC delta CF) in cells is associated with the appeara nce of certain characteristics of apoptosis. However, the functional r elationship between PKC delta cleavage and induction of apoptosis is u nknown. The present studies demonstrate that PKC delta associates cons titutively with the DNA-dependent protein kinase catalytic subunit (DN A-PKcs). The results show that PKC delta CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs with PKC delta CF inhibits the functio n of DNA-PKcs to form complexes with DNA and to phosphorylate its down stream target, p53. The results also demonstrate that cells deficient in DNA-PK are resistant to apoptosis induced by overexpressing PKC del ta CF. These findings support the hypothesis that functional interacti ons between PKC delta and DNA-PK contribute to DNA damage-induced apop tosis.