There is compelling evidence indicating that TGF-beta has a predominant growth inhibitory effect in normal epithelial cells and serves as a tumor suppressor. Neoplastic transformation results in loss of this growth inhibitory response. Human colon cancers are in general functionally resistant to TGF-beta growth inhibition. Resistance to TGF-betas in colorectal cancers can occur through a variety of mechanisms. First, mutations that inactivate TGF-beta type II receptor (TBRII) and thereby induce TGF-beta resistance are detected in 28% of all human colon cancers. Second, reduced expression of the TGF-beta receptors has been implicated as a mechanism for TGF-beta resistance in human colon tumors. Third, inactivating mutations of either Smad2 (7%) or Smad4 (20%) lead to a TGF-beta resistant state in human colon cancers. Therefore, functional inactivation of TGF-beta signaling components is associated with 55% of human colorectal cancers. It is still unknown how colon cancers become resistant to the antiproliferative response to TGF-beta in the other 45% of cases. Recently, we have identified a novel WD-domain protein STRAP that functions as an inhibitor of TGF-beta signaling, both alone and synergistically with the inhibitory Smad, Smad7. Smad7 is upregulated in pancreatic cancer, and STRAP is upregulated in 45% of breast cancers and in 60% of colorectal cancers. We hypothesize that abrogation of TGF-beta-induced growth arrest by the synergistic effects of STRAP and Smad7 provides a fourth mechanism by which human colon tumors become non-responsive to TGF-beta. We further hypothesize that functional cooperation between STRAP and Smad7 in growth promoting effects, and in blocking TGF-beta tumor suppressor function, is involved in colorectal carcinomas. The following specific aims are proposed to test these hypotheses. (1) Determine the role of STRAP on Smad7-mediated blockade of grown inhibition by TGF-beta. (2) Determine the roles of STRAP and Smad7 in ERK1/2 activation, in p21Cip1 downregulation, in cellular proliferation, and in tumorigenicity. (3) Examine the expression of STRAP and Smad7 in different stages and grades of colorectal cancer, and determine how STRAP- and Smad7-mediated abrogation of TGF-beta tumor suppressor effects is involved in colorectal tumor development and progression. The long term objectives of this study are to understand, at the molecular level, the mechanism by which a portion of colorectal cancers become resistant to TGF-beta tumor suppressor effects, and how functional cooperation between STRAP and Smad7 is involved in the transition from colonic polyp to metastatic carcinoma. This study will enhance our understanding of colorectal cancer biology, which will lead to the identification of new molecular targets, and should improve treatment and prevention strategies.
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