SIGNAL TRANSDUCTION AND CELL DEATH REGULATION

Project Details

Description

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.
StatusFinished
Effective start/end date1/01/0131/12/01