Novel Fas/CD95 Signaling Mechanisms

新颖的 Fas/CD95 信号传导机制

• 批准号: 7688490
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688490
• 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; Cysteine; Development; Disease; Down-Regulation; Employee Strikes; Event; Genes; HMGA2 gene; In Vitro; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Modification; Molecular Weight; Pathway interactions; Post-Translational Protein Processing; Process; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; 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; meetings; mouse model; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; palmitoylation; public health relevance; receptor internalization; research study; response; 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（CD 95/APO-1）介导许多组织中的细胞凋亡。在其配体FasL的刺激下，它形成由衔接分子FADD、引发剂半胱天冬酶8和10以及半胱天冬酶-8/10调节剂c-FLIP组成的死亡诱导信号复合物（DISC）。最近已经清楚，除了作为死亡受体的作用，Fas具有多种非凋亡活性，包括使Fas凋亡抗性癌细胞更具移动的和侵袭性的作用。这些新的活动也依赖于DISC成分，这引发了如何选择参与细胞凋亡或非细胞凋亡信号通路的问题。我们最近表明，Fas需要内化到一个内体/溶酶体室，以信号细胞凋亡。然而，在鲜明的对比，我们发现，受体内化是不需要通过Fas的非凋亡信号。我们发现，酪氨酸291参与调节Fas的内化，而另一个翻译后修饰，半胱氨酸199的棕榈酰化，有利于形成高分子量的DISC复合物（hiDISC）。hiDISC在Fas内化位点形成。最近，我们发现Fas抑制microRNA let-7的表达，并且我们获得了let-7通过靶向HMGA 2和IMP-1驱动肿瘤进展的证据。我们推测Fas的两个翻译后修饰决定Fas是否被内化，以及它是否激活凋亡或非凋亡信号通路，导致let-7下调。对Fas内化的作用和机制、翻译后修饰对Fas内化的调控以及Fas对let-7表达的调控等的研究，为中和Fas的促肿瘤活性提供了新的途径。我们提出以下三个具体目标：目标1：确定调节Fas信号细胞凋亡或生存的机制。目的2：描述Fas和let-7之间的功能联系。目的3：阐明Fas信号突变体和Fas调控的miRNAs在小鼠卵巢癌模型中的作用。表征Fas的非凋亡信号传导的新机制和功能后果可能有助于开发合理的策略和治疗方法，用于干扰癌症和其他疾病中失调的Fas信号传导。公共卫生关系：死亡受体Fas（CD 95/APO-1）在许多组织中被认为是凋亡的介导者，但Fas具有多种非凋亡活性，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信号传导凋亡或非凋亡途径的受体内化以及肿瘤抑制microRNA的下调。这些研究将为理解Fas的不同信号传导活性提供基础，并为干扰癌症和其他疾病中失调的Fas信号传导设计新的治疗方法。