Research Interests:
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 PKCd is an early and essential regulator of apoptosis in salivary epithelial cells and that
PKCd may function upstream of the mitochondria as an integrator of diverse death signals. Using techniques to
localize PKCd in cells undergoing apoptosis, we have shown that PKCd translocates to the nucleus in apoptotic cells,
and we have identified a nuclear localization sequence in PKCd that is required for nuclear translocation. Our goal
now is to understand the molecular mechanisms by which PKCd is activated during apoptosis and to identify nuclear
phosphorylation targets of PKCd in apoptotic cells. Current studies are also underway to explore the role of PKCd
in tumor promotion in the mammary and salivary gland, and to understand how PKC isoforms regulate mammary gland
development.
Selected Publications
DeVries, T.A., Neville, M.C. and Reyland, M.E. 2002. Nuclear localization of PKCd is required for apoptosis: Identification of a novel nuclear import sequence. EMBO J, 22:6050-6060.
Matassa,A.A., Carpenter, L., Biden, T., Bell, R., and Reyland, ME. 2003. Inhibition of PKCa induces a PKCd-dependent apoptotic program in salivary epitheliel cells. Cell Death Differ, 10:269-277
DeVries, T.A., Kalkofen, R.L, Matassa, A.A. and Reyland, M.E. 2004. PKCd regulates apoptosis via activation of STAT1. J Biol Chem. 279:45603-45612.
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 Cd. Oncogene, 24:3067-3072
Humphries, M.J., Limesand, K., Schneider, J., Nakayama, K and Reyland, M.E. 2006. Suppression of apoptosis in the PKCd null mouse in vivo. J Biol Chem 281:9728-9737
DeVies-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., Ohm, A. M., Schaack, J., Adwan, T. S. and Reyland M. E. 2008 Tyrosine phosphorylation regulates nuclear localization of PKCd?? Oncogene, Manuscript in press.
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