Apoptosis is a program of cell death initiated by physiological stimuli and cellular toxins, and defects in this pathway are associated with a wide range of disorders. Genetic disruption of the apoptotic pathway is a common feature of tumor cells and may underlie the resistance of many tumors to chemotherapeutic drugs. In the salivary gland, disorders of apoptosis contribute to the development of salivary gland tumors and Sj?gren's syndrome, an autoimmune disorder. Signal transduction by serine/threonine protein kinases plays an essential role in apoptosis induced by a variety of stimuli. A long-term goal of my lab is to understand how protein kinase C (PKC) modulates salivary acinar cell apoptosis. In this application we will focus on understanding how one member of this family, PKCd, regulates apoptosis. In previous studies we have shown that PKCd is required for an early event in apoptosis induced by a wide variety of cell toxins. Furthermore, we have shown that PKCd translocates to the nucleus in response to apoptotic signals, and that nuclear PKCd is required for apoptosis. While these studies define an essential role for PKCd in salivary acinar cell apoptosis, we know little about how PKCd is activated in response to apoptotic signals, or how activated PKCd regulates the apoptotic machinery. We posit that phosphorylation of PKCd by an upstream tyrosine kinase(s) regulates its pro-apoptotic function and that activated PKCd translocates to the nucleus where it regulates the abundance or activity of key proteins in the apoptotic machinery.
In Aim 1 of this application we will explore the mechanism of PKCd tyrosine phosphorylation and its functional significance in apoptosis.
In Aim 2 we will ask if PKCd functions by activating downstream signal transduction pathways, with a particular focus on the Signal Transducer and Activator of Transcription (STAT) pathway.
In Aim 3 we will explore nuclear targets of PKCd in apoptotic cells. The identification of the pathways which regulate PKCd activation and downstream signaling in apoptotic cells will enable the development of strategies Aimed at promoting or inhibiting apoptosis in this tissue. Our results will also be applicable to apoptosis in other epithelial cell models, and may have important implications for the development of therapies directed against other epithelial derived tumors such as those that arise in the breast and pancreas. ? ?
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