The previous funding cycle for this competing renewal application showed that TGF(beta) receptor loss by mutation was a significant mechanism for generating tumor progression. Moreover, the applicant showed that the loss of autocrine inhibitory TGF(beta) signaling rather than response to exogenous TGF(beta) in the tumor environment was critical to tumor progression and loss of TGF(beta) tumor suppressive activity. Consequently, he has concentrated his studies on the autocrine responses of TGF(beta), which occur at low receptor occupancy, rather than the responses associated with exogenous TGF(beta) treatment which is purposely designed to generate receptor saturation. Results from this funding cycle of the project have confirmed the importance of autocrine TGF(beta) in controlling the establishment of G(0), cell cycle re-entry and apoptosis. He has also shown that autocrine TGF(beta) inhibition of cell cycle transit depends upon post-restriction point mechanisms in G(1) involving p21(WAF) while mechanisms of exogenous TGF(beta) inhibition occur prior to the restriction point and are directed at modulation of pRb phosphorylation. The applicant will now test the hypothesis that the signal transduction mechanisms associated with the autocrine TGF(beta) responses differ qualitatively from those induced by receptor saturation. He has also shown that autocrine TGF(beta) activity is critical to the establishment of a G(0) or quiescent state. He will now test the hypothesis that loss of autocrine TGF(beta) generates a defective quiescent state based on the inappropriate expression of """"""""free"""""""" E2F4 (rather than Rb family bound E2F4), which facilitates cell-cycle re-entry and shortens the G(1) phase of the cell cycle. Finally, he has shown that autocrine TGF(beta) is critical to apoptosis generated by growth factor and nutrient deprivation. He will now test the hypothesis that loss of autocrine TGF(beta) activity promotes cell survival both in vitro and in vivo through loss of the ability of cells to regulate phosphorylation of the Bad apoptotic promoting protein.
Specific Aims to test these hypotheses are: 1. Determine differences in signaling mechanisms by autocrine vs. exogenous TGF(beta). 2. Determine effects of loss of autocrine TGF(beta) in the establishment of growth arrest and cell cycle re-entry. 3. Determine effects of loss of autocrine TGF(beta) on apoptosis.
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