Role of Protein Kinase C Iota in Colon Carcinogenesis

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Colon cancer results from progressive
disregulation of the normal growth inhibitory, differentiation and apoptotic
signals in colonic epithelial cells. Our long-term goal is to understand the
role of protein kinase C (PKC) isozymes in colonic epithelial cell biology and
colon carcinogenesis. Several lines of evidence suggest that the atypical PKC
iota isoform (PKCi) plays an important promotive role in colon carcinogenesis.
First, PKC expression is elevated in colon tumors relative to uninvolved
colonic epithelium. Second, expression of PKCi protects cancer cells from
apoptosis by activating NF-kB. Third, PKCi plays a requisite role in the
transformation of intestinal epithelial cells by activated Ras, an oncogene
commonly mutated in colon cancer. Fourth, inhibition of PKCi activity by
dietary omega-3 fatty acids correlates with the cancer-preventive effects of
omega-3 fatty acids. Taken together these data indicate that PKCi plays a key
role in colon carcinogenesis by enhancing cell survival. We hypothesize that
PKCi protects colonic epithelial cells against apoptosis and that elevated PKCi
in the colonic epithelium will result in an increased susceptibility to colon
carcinogenesis. We have generated transgenic mice that express constitutively
active (ca) or dominant-negative (dn) mutant forms of PKCi in the colonic
epithelium and have detected a decrease in basal apoptosis in the colonic
epithelium of mice expressing caPKCi. In Specific Aim 1, we will determine the
role of PKCi in colonic epithelial cell homeostasis by further characterizing
our caPKCi and dnPKCi transgenic mice. Specific Aim 2 will assess the role of
PKCi in mediating the effects of K-ras on colonic epithelial cell homeostasis
and colon carcinogenesis in-vivo. Specific Aim 3 will determine the role of
PKCi in Ras transformation and NF-kB signaling in intestinal epithelial cells
in-vitro and in the colonic epithelium in-vivo. Specific Aim 4 will assess the
role of PKCi in dietary fat-mediated changes in colonic epithelial cell
homeostasis and colon carcinogenesis. These aims will be accomplished through
the use of complementary transgenic mouse and rat intestinal epithelial cell
models to assess the function of PKCi in the colonic epithelium.
StatusFinished
Effective start/end date4/1/023/31/08

ASJC

  • Medicine(all)