The long-term goal of this proposal is to understand the molecular and cellular mechanisms of protein kinase C and how these mechanisms are altered by cancer-associated mutations in members of this enzyme family to promote oncogenesis. Protein kinase C isozymes transduce the myriad of signals resulting from receptor-mediated hydrolysis of phospholipids, playing critical roles in diverse cellular functions The discovery in the 1980s that they are the receptors for the potent tumor promoting phorbol esters, led to the dogma that activation of protein kinase C by phorbol esters promotes tumorigenesis. However, the finding that long-term treatment with phorbol esters causes the degradation of protein kinase C opens this interpretation to question. Protein kinase C levels are aberrant in diverse cancers, and over 160 mutations in protein kinase C isozymes have been found in human cancers. However, whether protein kinase C isozymes function as tumor suppressors or oncogenes is not established. By understanding the molecular and cellular mechanisms of protein kinase C, and taking advantage of novel tools our lab has developed, we are poised to address this fundamental question. Thus, a central hypothesis driving this proposal is that protein kinase C may be a tumor suppressor, with inactivation (rather than activation, as is the dogma) of the kinase promoting oncogenic pathways.
Three Aims are proposed: 1] to advance knowledge on the molecular mechanisms of protein kinase C, 2] to understand protein kinase C signaling in cells, and 3] to examine how cancer-associated mutations in protein kinase C alter its function, testing the hypothesis that protein kinase C may be a tumor suppressor rather than oncogene.
This research is relevant to public health because it addresses the basic molecular mechanisms of a key enzyme that controls cell signaling pathways that are often misregulated in disease. Specifically, our lab has advanced knowledge on the molecular basis of a class of enzymes, the protein kinase C family, whose members are the target of tumor promoting phorbol esters. In this proposal, we expand and apply our knowledge of the mechanisms of protein kinase C to understand how mutations in these enzymes that have been identified in human cancers promote oncogenesis, which may enable us to more effectively target this kinase in the treatment of cancer.
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|Newton, Alexandra C; Brognard, John (2017) Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor. Trends Pharmacol Sci 38:438-447|
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|Newton, Alexandra C; Tanzi, Rudolph E; VanHook, Annalisa M (2016) Science Signaling Podcast for 10 May 2016: PKC? in Alzheimer's disease. Sci Signal 9:pc11|
|McSkimming, Daniel Ian; Dastgheib, Shima; Baffi, Timothy R et al. (2016) KinView: a visual comparative sequence analysis tool for integrated kinome research. Mol Biosyst 12:3651-3665|
|Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47|
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