Apoptosis by FADD in normal and cancerous cells

描述（由申请人提供）：细胞凋亡调控缺陷被认为是癌症发展的先决条件，然而凋亡通路缺陷的性质尚不清楚。识别和理解在癌症发展过程中选择性中断的凋亡通路可能为癌症发展提供新的见解，并确定新的治疗靶点。我们正在研究一种由接头蛋白FADD （FADD- dd）死亡结构域诱导的新的细胞凋亡途径。这种途径具有不同寻常的特征，表明它是乳腺癌或前列腺癌发生时必须被破坏的细胞凋亡途径的一个例子。我们之前的研究表明，FADD-DD仅能诱导正常上皮细胞凋亡。这种细胞类型特异性反应通过一种先前未被认识的机制起作用，该机制与FADD的既定作用模式分开，可能涉及一种名为PL31的新型FADD结合蛋白。当上皮细胞变得永生化时，这种新途径被特异性地破坏。然而，这种破坏与参与永生的已知途径（p53， Rb和端粒酶）的失活无关。在正常细胞中，一种致癌基因（SV40 T抗原）可以赋予对这一凋亡途径的抗性，而不影响其他凋亡机制，而一种特异性肿瘤抑制因子（Bin1）可以赋予癌细胞对这一途径的敏感性。内源性FADD蛋白在TRAIL刺激下可激活该通路。因此，我们已经确定了一种新的凋亡途径，该途径由TRAIL激活，涉及FADD，可能涉及PL31和Bin1，并通过与细胞永生相关的p53和Rb独立机制被SV40 T抗原特异性破坏。这些数据将引导我们发展我们的假设：FADD参与了一种新的凋亡途径，该途径在乳腺癌或前列腺癌的发展过程中被特异性破坏。本文验证了这一假设，并确定了PL31、Bin1、T抗原和TRAIL的作用，目的如下：1)确定FADD-DD如何诱导正常上皮细胞凋亡。2)。确定为什么不死细胞抵抗fadd - dd诱导的细胞凋亡。3)。表征激活正常上皮细胞中fadd - dd依赖通路的生理信号。这些研究应该提供一个详细的了解以前未被认识到的凋亡途径，可能密切参与癌症的发展。

DESCRIPTION (provided by applicant): 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.