PROTEIN KINASE C AND COLON CARCINOGENESIS

Project: Research project

Project Details

Description

Colon carcinogenesis is a complex, multi-step process involving
progressive changes in intestinal epithelial cell proliferation,
differentiation and programmed death. Our long-term goal is to
understand the role of protein kinase C (PKC) isozymes in intestinal
epithelial cell biology and colon carcinogenesis. Several lines of
evidence suggest that the PKC betaII isozyme (PKC betaII) is involved
in colon carcinogenesis. First, PKC betaII levels and activity are
elevated in colon carcinomas compared to normal colonic epithelium.
Second, PKC betaII is involved in colon carcinoma cell proliferation in
vitro. Third, components of a high fat diet can potently stimulate
intestinal epithelial cell PKC betaII activity and promote colon
carcinogenesis. Based on these findings, and our preliminary studies,
we hypothesize that PKC betaII is directly involved in colon
carcinogenesis. To directly test this hypothesis, we developed
transgenic mice that express elevated PKC betaII levels in the
intestinal epithelium. In preliminary studies, these mice exhibit
evidence of colonic epithelial hyperproliferation and an increased
susceptibility to carcinogen-induced colon cancer. In this application
we propose four specific aims to: 1) characterize three transgenic PKC
betaII lines for transgene copy number, tissue distribution, expression
level and activity of the PKC betaII transgene, and for changes in
intestinal epithelial cytokinetics; 2) assess whether transgenic PKC
betaII mice exhibit increased susceptibility to carcinogen-induced colon
cancer; 3) determine whether a high fat diet enhances the susceptibility
of transgenic PKC betaII mice to colon cancer; and 4) determine whether
elevated PKC betaII expression synergizes with loss-of-function mutation
of the APC tumor suppressor gene in promoting intestinal tumorigenesis
in the APCmin mouse model. These studies will allow the first direct
analysis of the role of PKC betaII in colon cancer in two relevant
animal models of the human disease.
StatusFinished
Effective start/end date4/2/994/30/18

Funding

  • National Cancer Institute: $391,250.00
  • National Cancer Institute: $424,034.00
  • National Cancer Institute: $479,004.00
  • National Cancer Institute: $414,986.00
  • National Cancer Institute: $413,742.00
  • National Cancer Institute: $425,339.00
  • National Cancer Institute: $425,775.00
  • National Cancer Institute: $391,250.00
  • National Cancer Institute: $335,038.00
  • National Cancer Institute: $44,972.00
  • National Cancer Institute: $391,250.00
  • National Cancer Institute: $417,869.00
  • National Cancer Institute: $479,004.00
  • National Cancer Institute
  • National Cancer Institute: $324,417.00
  • National Cancer Institute: $430,738.00
  • National Cancer Institute: $438,109.00
  • National Cancer Institute: $648,014.00
  • National Cancer Institute: $422,576.00
  • National Cancer Institute: $470,306.00
  • National Cancer Institute: $391,250.00
  • National Cancer Institute: $379,513.00
  • National Cancer Institute: $351,104.00

ASJC

  • Medicine(all)

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