PKC regulation of salivary acinar cell apoptosis

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An increase or decrease in apoptosis is likely to contribute to the pathology of a wide range of disorders including those associated with development, autoimmune disease and cancer. In the salivary gland, disorders of apoptosis are likely to contribute to the genesis of salivary gland tumors, as well as Sjogren's syndrome, and autoimmune disorder. In addition, the apoptosis of normal salivary cells in patients treated with head and neck irradiation or chemotherapeutics can result in reduced salivary gland function, or xerostomia. Understanding the mechanisms which regulate apoptosis may suggest avenues for the development of novel therapeutics directed at either enhancing or suppressing apoptosis. The protein kinase C (PKC) family of signaling molecules consists of 11 isoforms some of which are thought to play specific roles cell proliferation and cell death. The long-term goal of this proposal is to understand how PKC modulates salivary gland acinar cell apoptosis. The studies described here will use cultures of primary salivary acinar cells, as well as two well differentiated salivary acinar cell lines from the rat parotid and sub-mandibular gland, to explore the hypothesis that activation of specific isoforms of PKC can promote or suppress apoptosis in response to chemotherapeutic drugs, X-irradiation and FAS ligand. Our preliminary results have identified candidate pro-apoptotic (PKCdelta and PKCalpha) PKC isoforms in salivary acinar cells. In AIM 1 we will determine if PKCalpha, PKCbeta1, and/or PKCdelta are activated in primary salivary cells undergoing apoptosis. We will use dominant negative mutants of PKCalpha and PKCdelta to ask if activation of these isoforms is essential for apoptosis. The studies in AIM 2 will focus on understanding how PKCdelta is activated during apoptosis. In AIM 3 we will ask how pro-apoptotic PKC isoforms promote apoptosis by characterizing molecules which function upstream and downstream of PKC in the apoptotic pathway. In addition to the specific application of these studies to salivary acinar cells, this model represents an alternative system in which to study the molecular mechanisms of epithelial cell apoptosis. Thus the information derived from these studies may also have important implications for the development of therapies directed against other epithelial derived tumors such as those of the breast and pancreas.