Signal transduction by serine/threonine protein kinases plays an essential role in apoptosis induced by a variety of stimuli. The long- term goal of my lab is to understand how PKC8 modulates salivary gland acinar cell apoptosis. Previous studies from our laboratory have defined an essential role for PKC8 in salivary acinar cells apoptosis induced by a wide variety of cell toxins. Expression of a dominant negative form of PKC8 results in inhibition of apoptosis at, or prior to, the mitochondria, indicating that PKC8 is required for an event early in the apoptotic pathway. We hypothesize that PKC8 is a common intermediate in mitochondrial dependent apoptosis in salivary epithelial cells, and that phosphorylation of PKC8 by an upstream regulatory kinase(s) initiates it's pro-apoptotic function. The mechanism of this phosphorylation event will be explored in the experiments proposed in this application. Aim I will identify specific residues of PKC8 phosphorylated in response to apoptotic stimuli. In Aim 2 we will use site-specific mutants of PKCB to determine the functional significance of PKC8 phosphorylation in apoptotic cells. Understanding the mechanisms that regulate early apoptotic events may suggest avenues for the development of novel therapeutics directed at either enhancing or suppressing apoptosis.

F33DE014314

2001-09-15

1900-01-01