Apoptosis by FADD in normal and cancerous cells

正常细胞和癌细胞中 FADD 导致的细胞凋亡

• 批准号: 7021465
• 负责人: Andrew M Thorburn
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-22 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021465
• 关键词: CD95 molecule; antigens; apoptosis; binding proteins; breast neoplasms; cell transformation; cytokine receptors; fluorescence microscopy; genetically modified animals; laboratory mouse; mammary epithelium; microinjections; neoplastic cell; neoplastic process; oncogenes; prostate; prostate neoplasms; protein protein interaction; tissue /cell culture; tumor necrosis factor alpha; tumor suppressor proteins; virus antigen

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.

描述（由申请人提供）：细胞凋亡调节缺陷被认为是癌症发展的先决条件，然而，对缺陷的细胞凋亡途径的性质知之甚少。识别和理解在癌症发展过程中被选择性破坏的凋亡途径可能会为癌症发展提供新的见解，并确定新的治疗靶点。我们正在研究一种新的凋亡途径，是由死亡结构域的衔接蛋白FADD（FADD-DD）。这种途径具有不寻常的特征，表明它是乳腺癌或前列腺癌发展必须被破坏的细胞凋亡途径的一个例子。我们前期的研究表明，FADD-DD只在正常上皮细胞中诱导凋亡。这种细胞类型特异性反应通过一种以前未被认识的机制起作用，该机制与FADD的既定作用模式不同，可能涉及一种称为PL 31的新型FADD结合蛋白。当上皮细胞永生化时，这种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。癌基因（SV 40 T抗原）可以在正常细胞中赋予对该凋亡途径的抗性而不影响其他凋亡机制，而特异性肿瘤抑制因子（Bin 1）可以在癌细胞中赋予对该途径的敏感性。当内源性FADD蛋白被TRAIL刺激时，它可以激活该通路。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PL 31和Bin 1，并通过与细胞永生化相关的p53和Rb独立机制被SV 40 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参与一种新的凋亡途径，该途径在乳腺癌或前列腺癌发展过程中被特异性破坏。在此，我们测试这一假设，并确定PL 31，Bin 1，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的凋亡。2）。确定为什么永生细胞对FADD-DD诱导的凋亡有抵抗力。3）。表征激活正常上皮细胞中FADD-DD依赖性通路的生理信号。这些研究应该提供一个以前未被认识的细胞凋亡途径，可能密切参与癌症的发展详细的了解。