Defects in apoptosis regulation are thought to be a prerequisite for cancer development however the nature of the apoptotic pathways that are defective is poorly understood. The identification and understanding of apoptotic pathways that are selectively disrupted during cancer development may provide new insights into cancer development and identify novel therapeutic targets. We are studying a novel apoptosis pathway that is induced by the death domain of the adaptor protein FADD (FADD-DD). This pathway has unusual characteristics that suggest it is an example of an apoptosis pathway that has to be disrupted for breast or prostate cancer to develop. Our previous studies show that FADD-DD can induce apoptosis only in normal epithelial cells. This cell type-specific response works via a previously unrecognized mechanism that is separate from the established mode of action of FADD and may involve a novel FADD-binding protein called PL31. The novel pathway is specifically disrupted when epithelial cells become immortalized. However, this disruption is unrelated to inactivation of the known pathways (p53, Rb & telomerase) that are involved in immortalization. An oncogene (SV40 T antigen) can confer resistance to this apoptosis pathway in normal cells without affecting other apoptosis mechanisms, while a specific tumor suppressor (Bin1) can confer sensitivity to this pathway in cancer cells. Endogenous FADD protein can activate this pathway when it is stimulated by TRAIL. Thus, we have identified a new apoptosis pathway that is activated by TRAIL, involves FADD, may involve PL31 and Bin1 and is specifically disrupted by SV40 T antigen through a p53- and Rb independent mechanism that is associated with cell immortalization. This data will lead us to develop our hypothesis: FADD participates in a novel apoptotic pathway that is specifically disrupted during breast or prostate cancer development. Here, we test this hypothesis and determine the roles of PL31, Bin1, T antigen and TRAIL with the following aims: 1) Determine how FADD-DD induces apoptosis of normal epithelial cells. 2). Determine why immortal cells are resistant to FADD-DD-induced apoptosis. 3). Characterize the physiologic signal that activates the FADD-DD-dependent pathway in normal epithelial cells. These studies should provide a detailed understanding of a previously unrecognized apoptosis pathway that may be intimately involved in cancer development.
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