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: 7175308
• 负责人: Andrew M Thorburn
• 金额: $ 28.84万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175308
• 关键词: Adaptor Signaling Protein; Affect; Agonist; Apoptosis; Apoptotic; Binding Proteins; Breast; Cancerous; Cell Death; Cells; Cessation of life; Characteristics; Data; Death Domain; Defect; Development; Disruption; Epithelial; Epithelial Cells; FADD protein; Growth; Large T Antigen; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Mutation; Nature; Normal Cell; Oncogenes; Paper; Pathway interactions; Phenotype; Physiological; Prostate; Proteins; Regulation; Resistance; Role; SV40 T Antigens; Signal Pathway; Signal Transduction; Simian virus 40; Stimulus; TNF-related apoptosis-inducing ligand; TP53 gene; Telomerase; Testing; Therapeutic Intervention; Thinking; Tumor Suppressor Proteins; Viral Tumor Antigens; Work; adapter protein; cancer cell; caspase-8; cell immortalization; cell type; insight; neoplastic cell; novel; novel therapeutics; prevent; receptor; response; sialosyl-T antigen; therapeutic target; tumor

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）：凋亡调节中的缺陷被认为是癌症发展的先决条件，但是缺陷的凋亡途径的性质知之甚少。在癌症发育过程中选择性破坏凋亡途径的识别和理解可以为癌症发展提供新的见解，并确定新颖的治疗靶标。我们正在研究一种新型的凋亡途径，该途径是由适配器蛋白FADD（FADD-DD）的死亡结构域诱导的。该途径具有不寻常的特征，表明它是凋亡途径的一个例子，必须破坏乳腺癌或前列腺癌才能发展。我们先前的研究表明，FADD-DD只能在正常上皮细胞中诱导凋亡。这种细胞类型特异性响应通过先前未认可的机制起作用，该机制与FADD的确定作用方式分开，可能涉及一种称为PL31的新型FADD结合蛋白。当上皮细胞永生化时，新型途径被特异性破坏。但是，这种破坏与与永生化有关的已知途径（p53，RB和端粒酶）失活无关。致癌基因（SV40 T抗原）可以在正常细胞中赋予这种凋亡途径的耐药性，而不会影响其他凋亡机制，而特定的肿瘤抑制剂（BIN1）可以赋予癌细胞中该途径的敏感性。内源性FADD蛋白可以在被TRAIL刺激时激活该途径。因此，我们已经确定了一种由TRAIL激活的新凋亡途径，涉及FADD，可能涉及PL31和BIN1，并通过p53-和RB独立机制特别破坏了SV40 T抗原，与细胞不朽相关。这些数据将导致我们提出假设：FADD参与了一种新的凋亡途径，该途径在乳腺癌或前列腺癌发展过程中受到了特殊破坏。在这里，我们检验了该假设，并确定PL31，BIN1，T抗原和Trail的作用，其目的是：1）确定FADD-DD如何诱导正常上皮细胞的凋亡。 2）。确定为什么不朽的细胞对FADD-DD诱导的细胞凋亡具有抗性。 3）。表征激活正常上皮细胞中FADD-DD依赖性途径的生理信号。这些研究应详细了解可能与癌症发展密切相关的先前未识别的细胞凋亡途径。