SIGNAL TRANSDUCTION AND CELL DEATH REGULATION

Caspases, a family of cysteine proteases, are central to most cell death programs and therefore present an attractive target for therapeutic interventions. The investigators have shown that the PKC signal transduction pathway regulates anticancer drug sensitivity although the mechanism of regulation is incompletely understood. There are three classes of PKC isozymes-conventional (alpha, beta1, beta2 and gamma), novel (delta, epsilon, eta, theta and mu) and atypical (zeta and lambda / iota). Novel PKC isozymes are substrates for caspases and proteolytic activation of these isozymes has been linked to cell death. The preliminary study showed that PKC can also influence activation of caspases by apoptotic stimuli, suggesting that the PKC signal transduction pathway can be targeted to increase cell death by apoptotic stimuli. The investigators hypothesize that PKC functions not only downstream of caspases but also upstream of caspases to regulate caspase activation and cell death by chemotherapeutic drugs and that both the catalytic fragment and holoenzyme of PKC decide cell survival and cell death. The Specific Aims are: (1) to delineate which steps of the cisplatin-induced caspase cascade are regulated by PKC; (2) to determine the functional significance of PKC activation and down-regulation on cisplatin-induced cell death and; (3) to establish whether deregulation in the PKC signal transduction pathway affects caspase activation and cisplatin resistance.