Novel Fas/CD95 Signaling Mechanisms

新颖的 Fas/CD95 信号传导机制

• 批准号: 7589350
• 负责人: Marcus E. Peter
• 金额: $ 27.57万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589350
• 关键词: Address; Affect; Apoptosis; Apoptotic; Automobile Driving; CASP8 and FADD-like apoptosis regulating protein; CD95 Antigens; Cell surface; Cells; Cessation of life; Characteristics; Choices and Control; Complex; Condition; Cysteine; Development; Disease; Down-Regulation; Employee Strikes; Event; Genes; HMGA2 gene; In Vitro; Invasive; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Modification; Molecular Weight; Numbers; Pathway interactions; Post-Translational Protein Processing; Process; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Public Health; Receptor Signaling; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Site; System; Testing; Therapeutic; Tissues; Tyrosine; base; cancer cell; caspase-8; cell killing; cell motility; design; mouse model; mutant; neoplastic cell; novel; novel therapeutics; palmitoylation; receptor internalization; research study; response; therapeutic target; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): The death receptor Fas (CD95/APO-1) mediates apoptosis in many tissues. Upon stimulation by its ligand FasL, it forms a death inducing signaling complex (DISC) consisting of the adaptor molecule FADD, the initiator caspases 8 and 10, and the caspase-8/10 regulator c-FLIP. Recently it has become clear that, in addition to its role as a death receptor, Fas has multiple nonapoptotic activities including a role in rendering Fas apoptosis-resistant cancer cells more mobile and invasive. These novel activities also rely on DISC components, raising the question of how the choice to engage apoptotic or nonapoptotic signaling pathways is made. We have recently shown that Fas requires internalization into an endosomal/lysosomal compartment in order to signal apoptosis. However, in striking contrast, we found that receptor internalization is not required for nonapoptotic signaling through Fas. We found that tyrosine 291 is involved in regulating the internalization of Fas and that another postranslational modification, palmitoylation of cysteine 199, facilitates the formation of high molecular weight DISC complexes (hiDISC). hiDISC forms at the sites of Fas internalization. Recently, we found that Fas suppresses the expression of the microRNA let-7 and we obtained evidence that let-7 drives tumor progression through targeting HMGA2 and IMP-1. We hypothesize that the two posttranslational modifications of Fas determine whether Fas is internalized and whether it activates apoptotic or nonapoptotic signaling pathways resulting in downregulation of let-7. Identification of the role and the mechanisms of the internalization of Fas, its regulation by posttranslational modifications, and the regulation of let-7 expression by Fas could provide the means to neutralize the tumor promoting activities of Fas. We propose the following three specific aims: Aim 1: Determine the mechanisms that regulate whether Fas signals apoptosis or survival. Aim 2: Characterize the functional connection between Fas and let-7. Aim 3: Elucidate the function of Fas signaling mutants and of Fas regulated miRNAs in mouse models of ovarian cancer. Characterization of the novel mechanisms and functional consequences of nonapoptotic signaling of Fas may facilitate the development of rational strategies and therapeutic approaches for interfering with dysregulated Fas signaling in cancer and other diseases. PUBLIC HEALTH RELEVANCE: The death receptor Fas (CD95/APO-1) has been viewed as a mediator of apoptosis in many tissues but it has become clear that Fas has multiple nonapoptotic activities including the induction of proliferation and tumor invasiveness. We will study the early events of Fas signaling including receptor internalization that determine whether Fas signals apoptotic or nonapoptotic pathways and downregulation of tumor suppressing microRNAs. These studies will provide a basis for understanding the different signaling activities of Fas and to devise new therapeutic approaches for interfering with dysregulated Fas signaling in cancer and other diseases.

描述（由申请人提供）：死亡受体Fas（CD95/APO-1）介导许多组织中的细胞凋亡。在其配体 FasL 刺激下，它形成死亡诱导信号复合物 (DISC)，由接头分子 FADD、引发剂 caspase 8 和 10 以及 caspase-8/10 调节剂 c-FLIP 组成。最近已经清楚，除了作为死亡受体的作用外，Fas 还具有多种非凋亡活性，包括使 Fas 抗凋亡癌细胞更具移动性和侵袭性。这些新的活性也依赖于 DISC 成分，这就提出了如何选择参与凋亡或非凋亡信号通路的问题。我们最近表明，Fas 需要内化到内体/溶酶体区室中才能发出凋亡信号。然而，与此形成鲜明对比的是，我们发现 Fas 的非凋亡信号传导不需要受体内化。我们发现酪氨酸 291 参与调节 Fas 的内化，而另一种翻译后修饰，半胱氨酸 199 的棕榈酰化，促进高分子量 DISC 复合物 (hiDISC) 的形成。 hiDISC 在 Fas 内化位点形成。最近，我们发现Fas抑制microRNA let-7的表达，并获得let-7通过靶向HMGA2和IMP-1驱动肿瘤进展的证据。我们假设 Fas 的两种翻译后修饰决定 Fas 是否被内化以及它是否激活凋亡或非凋亡信号通路，从而导致 let-7 下调。鉴定Fas内化的作用和机制、翻译后修饰对Fas的调节以及Fas对let-7表达的调节可以提供中和Fas促肿瘤活性的方法。我们提出以下三个具体目标： 目标 1：确定调节 Fas 是否发出凋亡信号或存活信号的机制。目标 2：描述 Fas 和 let-7 之间的功能联系。目标 3：阐明 Fas 信号突变体和 Fas 调节的 miRNA 在卵巢癌小鼠模型中的功能。 Fas 非凋亡信号传导的新机制和功能后果的表征可能有助于制定合理的策略和治疗方法，以干扰癌症和其他疾病中失调的 Fas 信号传导。公共健康相关性：死亡受体 Fas (CD95/APO-1) 已被视为许多组织中细胞凋亡的介质，但现已明确 Fas 具有多种非细胞凋亡活性，包括诱导增殖和肿瘤侵袭。我们将研究 Fas 信号传导的早期事件，包括决定 Fas 是否发出凋亡或非凋亡途径信号的受体内化以及肿瘤抑制 microRNA 的下调。这些研究将为了解 Fas 的不同信号传导活动提供基础，并设计新的治疗方法来干扰癌症和其他疾病中失调的 Fas 信号传导。