The long-term goals of this application are (a) to define the function(s) of individual members of the protein kinase C (PKC) family of signal transduction molecules in regulation of intestinal epithelial self-renewal, and (b) to determine how alterations in PKC isozyme signaling pathways contribute to the development of intestinal disease. This renewal application draws on new information demonstrating that PKC/PKC a signaling triggers a coordinated program of cell cycle withdrawal in intestinal epithelial cells, that PKC alpha activity regulates survival pathways in this system, that desensitization of PKC a signaling appears to be an important component of intestinal carcinogenesis, and that loss of PKC/PKC a expression/activity promotes the growth of intestinal cells. Based on these findings, strategies are proposed in this application to test the hypothesis that PKC alpha is a key component of signaling pathways that regulate intestinal epithelial cell growth and cell survival, and that specific alterations in the activity/ expression of this molecule play a pivotal role in the development of intestinal neoplasia. Restoration of PKC a function may thus be of benefit for the prevention and/or therapy of intestinal tumors. To test this hypothesis, the following Specific Aims will be addressed: (1) To define the mechanisms involved in transcriptional induction of p21waf1/cip1 by PKC/PKC a signaling in intestinal epithelial cells and determine if p21waf1/cip1 regulatory pathways downstream of PKC alpha signaling are altered in neoplastic intestinal cells, (2) To determine the role of PKC a signaling in regulation of intestinal epithelial cell survival, (3) To define the molecular mechanisms underlying loss of PKC a expression during intestinal carcinogenesis, and (4) To explore the potential of differentiation agents with promising preventive and therapeutic activity in colon cancer (i.e., retinoids, vitamin D) to restore PKC alpha expression in neoplastic intestinal cells. These studies are expected to enhance our understanding of the signaling pathways that orchestrate the process of intestinal epithelial renewal and highlight the contribution of defects in PKC signaling to intestinal neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054909-07
Application #
6951411
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
May, Michael K
Project Start
1999-03-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
7
Fiscal Year
2006
Total Cost
$274,787
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Lum, Michelle A; Barger, Carter J; Hsu, Alice H et al. (2016) Protein Kinase C? (PKC?) Is Resistant to Long Term Desensitization/Down-regulation by Prolonged Diacylglycerol Stimulation. J Biol Chem 291:6331-46
Pysz, Marybeth A; Hao, Fang; Hizli, A Asli et al. (2014) Differential regulation of cyclin D1 expression by protein kinase C ? and ? signaling in intestinal epithelial cells. J Biol Chem 289:22268-83
Lum, Michelle A; Balaburski, Gregor M; Murphy, Maureen E et al. (2013) Heat shock proteins regulate activation-induced proteasomal degradation of the mature phosphorylated form of protein kinase C. J Biol Chem 288:27112-27
Fan, Chuan-Dong; Lum, Michelle A; Xu, Chao et al. (2013) Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response. J Biol Chem 288:1674-84
Lum, Michelle A; Pundt, Krista E; Paluch, Benjamin E et al. (2013) Agonist-induced down-regulation of endogenous protein kinase c ? through an endolysosomal mechanism. J Biol Chem 288:13093-109
Gogada, Raghu; Amadori, Michael; Zhang, Honghao et al. (2011) Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell Cycle 10:4128-37
Hao, Fang; Pysz, Marybeth A; Curry, Kathryn J et al. (2011) Protein kinase C? signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium. J Biol Chem 286:18104-17
Pysz, Marybeth A; Leontieva, Olga V; Bateman, Nicholas W et al. (2009) PKCalpha tumor suppression in the intestine is associated with transcriptional and translational inhibition of cyclin D1. Exp Cell Res 315:1415-28
Guan, Lingjie; Song, Kyung; Pysz, Marybeth A et al. (2007) Protein kinase C-mediated down-regulation of cyclin D1 involves activation of the translational repressor 4E-BP1 via a phosphoinositide 3-kinase/Akt-independent, protein phosphatase 2A-dependent mechanism in intestinal epithelial cells. J Biol Chem 282:14213-25
Hizli, A Asli; Black, Adrian R; Pysz, Marybeth A et al. (2006) Protein kinase C alpha signaling inhibits cyclin D1 translation in intestinal epithelial cells. J Biol Chem 281:14596-603

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