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Molecular Biology Program
 

Mary Reyland, Professor

Ph.D. (1983), Medical College of Virginia


 

 

 

 

Contact Info:

Molecular Biology
University of Colorado

Mary Reyland, Ph.D.  Research One South
(RC1-South), Room 11113
Mary.Reyland@ucdenver.edu Phone: 303-724-4572

 

 

 
 

Regulation of Cell Death by the Protein Kinase C Family: Implications for Tissue Damage and Tumorigenesis

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 a widely used 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 of lipid-regulated serine/threonine protein kinases function to modulate apoptosis. To explore the role of PKCd in these processes, we have use cultured epithelial cells or 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 disruption of the PKCd gene in mice results in resistance to irradiation-induced apoptosis in multiple tissues in vivo. Based on these studies we hypothesize that PKCd functions upstream of the mitochondria as an integrator of diverse death signals. As disruption of apoptosis contributes to cancer promotion/ progression, we have recently initiated studies to understand the role of protein kinase C in these processes. Surprisingly, our studies indicate that the loss of PKCd suppresses tumor formation in both the lung and the mammary gland through mechanisms that are independent of apoptosis. This exciting data suggests that PKCd can regulate signal transduction pathways that promote cell transformation and cancer cell growth.

Current projects in the lab:

  1. Exploring the mechanism by which PKCd regulates apoptosis. 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 model suggests that retention of PKCd in the cytoplasm is consistent with cell survival and proliferation, while nuclear import signals cell death.
    • We are currently deciphering the mechanisms by which PKCd is activated during apoptosis using a structure/function approach to identify binding sites for PKCd interacting proteins. We hypothesize that such interactions may retain PKCd in the cytoplasm in the absence of an apoptotic signal.
    • Previous studies in the lab have shown that tyrosine phosphorylation of PKCd also regulates its sub-cellular localization; we are currently exploring the affect of tyrosine phosphorylation at specific sites on the localization and function of PKCd .
    • A long term goal of this project is to identify nuclear phosphorylation targets of PKCd in apoptotic cells using substrate tagging strategies.
  2. Exploring the role of PKCd in tumor promotion and progression. Our data from lung and mammary gland models of cancer suggests that PKCd can regulate signal transduction pathways that promote cell transformation and cancer cell growth, particularly the Ras/Raf/MEK1/ERK pathway.
    • We would like to understand mechanistically how PKCd regulates ERK and other proliferative signaling in lung and breast cancer cells.
    • The ability of tumors cells to grow in a three-dimensional matrix requires PKCd; this likely requires extracellular matrix interactions involving integrins, fibronectins, etc. Does PKCd regulate the interaction of cancer cells with the extracellular environment?
    • Can we translate our mouse studies to the human disease? Is PKCd expression/activation/localization altered in human tumors?
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Brittany Allen-Petersen (CDSV graduate program)
Tariq Adwan (CDSV graduate program)
Jennifer Symonds (CANB graduate program)
Gregg Banninger (Postdoctoral Associate)