Project: Research project

Project Details


DESCRIPTION: Accordingly, the overall goal of the current proposal involves
elucidation of mechanisms underlying signaling of specific TGFb responses in
intestinal epithelial cells (IEC's) and human colon carcinoma cells
(HCCC's). A clearer understanding of the signaling components regulated by
TGFb will ultimately facilitate efforts to identify deficiencies in such
cellular components associated with colon cancer progress. In this
proposal, the hypothesis that the major classes of TGFb responses in IEC's
and HCCC's are dependent upon the activities of the signaling components Ras
and Erk will be tested. More specifically, inducible expression of
dominant-negative mutant versions of Ras and Erk2 will be employed as tools
to assess the role of these signaling components in mediating specific TGFb
responses in IEC's and HCCC's, i.e., growth inhibition, repression of the
activity of the cell cycle component cyclin-dependent kinase 2 (Cdk2),
up-regulation of the Cdk inhibitor p21Cip1, production of the extracellular
matrix protein fibronectin and its receptors (integrins), induction of the
colon cell differentiation marker carcinoembryonic antigen, and modulation
of gene expression. Additional studies involving transfection of autocrine
TGFb-positive and negative HCCC's with dominant-negative Erk2 will be used
to test the hypothesis that the TGF -mediated decreases in
anchorage-independent growth and tumorigenicity of the autocrine
TGFb-positive HCCC's are dependent upon the function of Erk2. Finally, the
investigators will examine whether alterations exit in TGF regulation of
mitogen- activated protein kinases (MAPK's) in TGFb-resistant HCCC's with
intact TGFb receptors.
Effective start/end date4/1/924/30/01


  • National Cancer Institute
  • National Cancer Institute


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