Mary E. Reyland Associate Professor Craniofacial Biology / Cell and Developmental Biology Ph.D., Medical College of Virginia, 1983 UCHSC at Fitzsimons RC1-South, Room 11113 P.O. Box 6511, Mail Stop 8120 Aurora, CO 80045 Phone: 303-724-4572 Fax: Email: Mary.Reyland@uchsc.edu

Role of protein kinase C signaling in programmed cell death

Apoptosis, or programmed cell death, is critical for vertebrate development, the clearance of damaged or genetically altered cells and is induced by a variety of exogenous agents including irradiation, chemotherapeutic drugs and cell toxins. The ability to evade apoptosis is considered a "hallmark" of cancer, and genetic disruption of the apoptotic pathway is a common feature of neoplasia. Phosphorylation of cellular proteins by protein kinases is utilized widely as a mechanism to relay information within the cell, a process known as "signal transduction". My laboratory is interested in how specific members of the protein kinase C (PKC) family function to modulate apoptosis. As a model we use salivary epithelial cells either in culture, or derived from genetically modified mice that have specific defects in protein kinase C directed signal transduction. Our studies have demonstrated that PKCδ is an early and essential regulator of apoptosis in salivary epithelial cells and that PKCδ may function upstream of the mitochondria as an integrator of diverse death signals. Using techniques to localize PKCδ in cells undergoing apoptosis, we have shown that PKCδ translocates to the nucleus in apoptotic cells, and we have identified a nuclear localization sequence in PKCδ that is required for nuclear translocation. Our goal now is to understand the molecular mechanisms by which PKCδ is activated during apoptosis and to identify nuclear phosphorylation targets of PKCδ in apoptotic cells. Current studies are also underway to explore the role of PKCδ in tumor promotion in the mammary and salivary gland, and to understand how PKC isoforms regulate mammary gland development.

Selected Publications

Humphries, M. J., Ohm, A. M., Schaack, J., Adwan, T. S. and Reyland M. E. 2008 Tyrosine phosphorylation regulates nuclear localization of PKCδ Oncogene, Manuscript in press.

DeVries-Seimon, T.A., Ohm, A. M., Humphries, M.J. and Reyland, M.E. 2007. Induction of apoptosis is driven by nuclear retention of protein kinase C delta. J Biol Chem 282:22307-22314.

Humphries, M.J., Limesand, K., Schneider, J., Nakayama, K and Reyland, M.E. 2006. Suppression of apoptosis in the PKCδ null mouse in vivo. J Biol Chem 281:9728-9737.

Jackson, D., Zheng, Y., Lyo, D., Nakayama, K., Nakayama, K.I., Humphries, M.J., Reyland, M.E. and Foster, D. A. 2005. Suppression of cell migration by protein kinase Cδ. Oncogene, 24:3067-3072.

DeVries, T.A., Kalkofen, R.L, Matassa, A.A. and Reyland, M.E. 2004. PKCδ regulates apoptosis via activation of STAT1. J Biol Chem. 279:45603-45612.

Matassa,A.A., Carpenter, L., Biden, T., Bell, R., and Reyland, ME. 2003. Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epitheliel cells. Cell Death Differ, 10:269-277.

DeVries TA, Neville MC, Reyland ME. Nuclear import of PKCdelta is required for apoptosis: identification of a novel nuclear import sequence. EMBO J. 2002 Nov 15;21(22):6050-6060.

Shizukuda Y, Reyland ME, Buttrick PM. Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes. Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1625-34.

Helt CE, Hoernig GR, Albeck DS, Gerhardt GA, Ickes B, Reyland ME, Quissell DO, Stromberg I, Granholm AC. Neuroprotection of grafted neurons with a GDNF/caspase inhibitor cocktail. Exp Neurol. 2001 Aug;170(2):258-69.

Matassa AA, Carpenter L, Biden TJ, Humphries MJ, Reyland ME. PKCdelta is required for mitochondrial-dependent apoptosis in salivary epithelial cells. J Biol Chem. 2001 Aug 10;276(32):29719-28.

Reyland ME, Barzen KA, Anderson SM, Quissell DO, Matassa AA. Activation of PKC is sufficient to induce an apoptotic program in salivary gland acinar cells. Cell Death Differ. 2000 Dec;7(12):1200-9.

Latest Publications in PubMed