Apoptosis is a process by which tumor cells, or cells damaged by viral infection, drugs, chemical radiation and aging, are destroyed. Apoptosis also plays a critical role in vertebrate development and glandular homeostasis. An increase or decrease in apoptosis is thought to contribute to the pathology of a wide range of disorders including those associated with development, autoimmune disease and cancer. Some key regulatory molecules in this pathway have been identified, including the Bcl-2 and caspase families. However it is clear that the apoptotic pathway can also be regulated by a variety of enzymes involved in signal transduction. Our laboratory is interested in how the protein kinase C (PKC) signal transduction pathway regulates apoptosis. PKC is a large family of enzymes that function to transduce signals from the cell surface to intracellular molecules. PKC activity in the cell is tightly regulated and activation requires specific co-factors including Ca++ and lipids. The activation of specific PKC isoforms has been shown to either promote, or protect against, apoptosis depending on the isoform and cell type. Our work demonstrates that the PKCd isoform is proteolytically cleaved and activated in response to agents that damage DNA and induce apoptosis. In addition, the expression of activated forms of PKCd in salivary acinar cells by transfection is sufficient to induce apoptosis in these cells. To determine whether activation of PKCd is required for apoptosis to occur, we have asked if specific chemical inhibitors of PKCd can block apoptosis in response to DNA damaging drugs. These studies show that inhibition of PKCd totally blocks apoptosis indicating that activation of PKCd is essential for apoptosis in response to DNA damaging agents. Our goal now is to understand the mechanism of this regulation and to identify targets which lie upstream and downstream of PKCd in this pathway. In addition, we are interested in exploring the function of other PKC isoforms during apoptosis.

Selected Publications

1. Swarnakar S, Reyland ME, Deng J, Azhar S. and Williams DL. 1998. Selective Uptake of LDL Cholesteryl Ester is Enhanced by Inducible Apolipoprotein E Expression in Cultured Mouse Adrenocortical Cells. J Biol Chem 273:12140-12147.
2. Reyland ME, Williams DL and White EK. 1998. Inducible expression of protein kinase Ca suppresses steroidogenesis in Y1 adrenocortical cells. Amer J Physiol 275:C780-C789.
3. Anderson SM, Reyland ME, Hunter S, Barzen KA, Deisher LM and Quissell DO. 1999. Etoposide-induced activation of c-jun N-terminal kinase (JNK) correlates with drug-induced apoptosis in salivary gland acinar cells. Cell Death and Differentiation, manuscript in press.
4. Reyland ME, Anderson SM, Matassa A, Quissell DO and Barzen KA. 1999. Protein kinase C-d is essential for etoposide-induced apoptosis in salivary acinar cells. J Biol Chem, Manuscript in press.