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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015648-03
Application #
6984114
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shum, Lillian
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
3
Fiscal Year
2006
Total Cost
$338,358
Indirect Cost
Name
University of Colorado Denver
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Keysar, Stephen B; Eagles, Justin R; Miller, Bettina et al. (2018) Salivary Gland Cancer Patient-Derived Xenografts Enable Characterization of Cancer Stem Cells and New Gene Events Associated with Tumor Progression. Clin Cancer Res 24:2935-2943
Ohm, A M; Tan, A-C; Heasley, L E et al. (2017) Co-dependency of PKC? and K-Ras: inverse association with cytotoxic drug sensitivity in KRAS mutant lung cancer. Oncogene 36:4370-4378
Wie, Sten M; Wellberg, Elizabeth; Karam, Sana D et al. (2017) Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-?. Mol Cancer Ther 16:1989-1998
Moua, Pachai; Checketts, Mathew; Xu, Liang-Guo et al. (2017) RELT family members activate p38 and induce apoptosis by a mechanism distinct from TNFR1. Biochem Biophys Res Commun 491:25-32
Symonds, Jennifer M; Ohm, Angela M; Tan, Aik-Choon et al. (2016) PKC? regulates integrin ?V?3 expression and transformed growth of K-ras dependent lung cancer cells. Oncotarget 7:17905-19
Reyland, Mary E; Jones, David N M (2016) Multifunctional roles of PKC?: Opportunities for targeted therapy in human disease. Pharmacol Ther 165:1-13
Allen-Petersen, B L; Carter, C J; Ohm, A M et al. (2014) Protein kinase C? is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer. Oncogene 33:1306-15
Wie, Sten M; Adwan, Tariq S; DeGregori, James et al. (2014) Inhibiting tyrosine phosphorylation of protein kinase C? (PKC?) protects the salivary gland from radiation damage. J Biol Chem 289:10900-8
Larroque-Cardoso, P; Swiader, A; Ingueneau, C et al. (2013) Role of protein kinase C ? in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells. Cell Death Dis 4:e520
Cusick, John K; Mustian, Andrea; Jacobs, Aaron T et al. (2012) Identification of PLSCR1 as a protein that interacts with RELT family members. Mol Cell Biochem 362:55-63

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