Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine protein kinases that play a central role in signal transduction. Work from Dr. Datta's laboratory has demonstrated that PKCdelta, theta and mu are proteolytically cleaved during DNA damage- induced apoptosis. His hypothesis is that PKCdelta, theta and mu are important mediators of the genotoxic stress response and that they contribute to the regulation of cell fate by inducing apoptosis. Once the cell death pathway is initiated, specific proteins are targeted for proteolytic cleavage by cysteine proteases. Among the known targets, PKCdelta and theta are the substrates whose cleaved catalytically active fragments induce an apoptotic phenotype. However, the biological significance of proteolytic cleavage and the mechanism by which such cleavage leads to apoptotic cell death is largely undefined. The proposed studies will explore the mechanisms involved in PKCdelta and theta - induced apoptosis. Localization of cleaved PKC products and identification of downstream effectors involved in the execution machinery will contribute towards our understanding of cell death pathways. The proposed work will also study the involvement of PKCmu, which is unique by its cleavage at two sites, in regulation of apoptosis. Thus, the proposed studies will focus on a relatively unexplored area of signaling that involves i) proteolytic activation of PKCs by caspases, and ii) the functional roles of specific PKC isoforms in induction of apoptosis.
The specific aims are 1) to define the functional significance of PKCdelta and theta cleavage in induction of apoptosis, 2) to study the functional interaction of PKCdelta and theta cleaved fragments with other proteins, and 3) to study the role of PKCmu in apoptosis.
| Ren, Jian; Datta, Rakesh; Shioya, Hisashi et al. (2002) p73beta is regulated by protein kinase Cdelta catalytic fragment generated in the apoptotic response to DNA damage. J Biol Chem 277:33758-65 |
| Majumder, P K; Pandey, P; Sun, X et al. (2000) Mitochondrial translocation of protein kinase C delta in phorbol ester-induced cytochrome c release and apoptosis. J Biol Chem 275:21793-6 |
| Endo, K; Oki, E; Biedermann, V et al. (2000) Proteolytic cleavage and activation of protein kinase C [micro] by caspase-3 in the apoptotic response of cells to 1-beta -D-arabinofuranosylcytosine and other genotoxic agents. J Biol Chem 275:18476-81 |
| Datta, R; Oki, E; Endo, K et al. (2000) XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. J Biol Chem 275:31733-8 |
| Datta, R; Yoshinaga, K; Kaneki, M et al. (2000) Phorbol ester-induced generation of reactive oxygen species is protein kinase cbeta -dependent and required for SAPK activation. J Biol Chem 275:41000-3 |
