Apoptosis by FADD in normal and cancerous cells

描述(申请人提供)：细胞凋亡调控的缺陷被认为是癌症发生的先决条件，然而，有缺陷的细胞凋亡通路的性质却知之甚少。识别和理解在癌症发展过程中被选择性干扰的凋亡通路可能为癌症的发展提供新的见解，并确定新的治疗靶点。我们正在研究一种由适配蛋白FADD的死亡结构域(FADD-DD)诱导的新的细胞凋亡途径。这一途径具有不同寻常的特征，这表明它是一个必须被破坏才能发展成乳腺癌或前列腺癌的细胞凋亡途径的例子。我们以前的研究表明，FADD-DD只在正常的上皮细胞中诱导细胞凋亡。这种细胞类型特异的反应通过一种以前未被认识的机制发挥作用，该机制独立于FADD的既定作用模式，并可能涉及一种名为PL31的新型FADD结合蛋白。当上皮细胞永生化时，这一新的途径被特异性地破坏。然而，这种破坏与参与永生化的已知途径(P53、RB和端粒酶)的失活无关。在正常细胞中，癌基因(SV40T抗原)可以在不影响其他凋亡机制的情况下对这一途径产生抵抗，而在癌细胞中，特异的肿瘤抑制因子(BIN1)可以使人对这一途径产生敏感性。内源性FADD蛋白在TRAIL刺激下可激活该通路。因此，我们发现了一种新的细胞凋亡途径，它由TRAIL激活，涉及FADD，可能涉及PL31和BIN1，并被SV40T抗原通过与细胞永生化相关的P53和Rb非依赖机制特异性地阻断。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地破坏。在这里，我们验证了这一假说，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)。确定为什么永生细胞对FADD-DD诱导的细胞凋亡具有抵抗力。3)。描述在正常上皮细胞中激活FADD-DD依赖通路的生理信号。这些研究应该提供对以前未知的可能与癌症发生密切相关的细胞凋亡途径的详细了解。

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.