This is a competitive renewal application for a project whose overall theme is the relationship between integrins, TGFbeta inhibitory response and malignant progression. Hypotheses for the previous period of support for this project were that integrin/ECM interactions modulate TGFbeta autocrine inhibitory activity and that dysfunction of these interactions contributes to malignant progression. During the past cycle of the project the applicant has found that both mutational inactivation of TGFbeta receptors as well as their repression by transcriptional inactivation provide mechanisms for loss of autocrine TGFbeta and malignant progression and that autocrine TGFbeta controlled steady state integrin and ECM levels. Cells with transcriptionally inactivated TGFbeta receptors were utilized to show that alpha5 integrin expression along with ligation to fibronectin led to expression of TGFbeta receptors, acquisition of autocrine TGFbeta activity and reversal of malignancy. Moreover, blockade of alpha5beta1 ligation resulted in stimulation of DNA synthesis and the reversal of TGFbeta1 inhibitory effects. Thus the applicant is now poised to determine how TGFbeta's and integrins converge in their control of DNA synthesis and proliferation. The renewal project focuses on two issues. The first is the mechanism by which alpha5beta1 ligation to FN stimulates TGFbeta receptor expression while the second issue is the mechanism by which disruption of alpha5beta1 ligation leads to stimulation of DNA synthesis. The applicant hypothesizes that integrin mediated signalling is responsible for TGFbeta receptor induction and that ligation of alpha5beta1 to FN facilitates TGFbeta inhibitory effects of the cell cycle.
Specific aims i nclude determination of the (1) structural regions of FN which contribute to control of TGFbeta receptor expression, (2) mechanism by which alpha5beta1 mediates TGFbeta receptor induction and (3) mechanism by which disruption of alpha5beta1 ligation leads to increased DNA synthesis and blockade of TGFbeta inhibition.
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