AMID in Apoptosis and p53-Mediated Downstream Effects

AMID 在细胞凋亡和 p53 介导的下游效应中的作用

• 批准号: 7092608
• 负责人: Philippa C. Marrack
• 金额: $ 27.31万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-14 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092608
• 关键词: apoptosis; athymic mouse; cell cycle; flavoproteins; gene expression; genetic promoter element; genetic regulation; genetically modified animals; guanine nucleotide binding protein; immunoprecipitation; mitochondria; neoplasm /cancer genetics; neoplastic transformation; p53 gene /protein; protein protein interaction; protein structure function; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Apoptosis is a cell suicide process involved in various physiological and pathological activities, such as embryonic development, cancer and autoimmune diseases. Induction of apoptosis can be mediated through both caspase dependent and independent processes. The mechanisms of caspase-independent apoptosis have not been well understood. AIF is a mitochondrial flavoprotein that triggers caspase-independent apoptosis. We have cloned a novel AIF homologous molecule designated as AMID. AMID is localized to the outer membrane of mitochondria. Overexpression of AMID induces caspase-independent apoptosis. Moreover, AMID is induced by the tumor suppressor p53 and expression of AMID is down-regulated in tumors in comparison to their individually matched normal tissues. We hypothesize that AMID induces caspase-independent apoptosis through novel mechanisms and AMID is a tumor suppressor involved in p53-mediated downstream effects. To test our hypotheses, we have proposed three specific aims: 1). To investigate the mechanisms of AMID-induced caspase-independent apoptosis; 2). To investigate the roles of AMID in p53-mediated apoptosis and cell growth arrest; 3). To determine whether AMID is a tumor suppressor gene using in vitro cell culture systems and in vivo gene knock-out studies in mice. Successful completion of the proposed studies will help to understand the molecular mechanisms of caspase-independent apoptosis and roles of AMID in p53-mediated biological effects and tumorigenesis.

描述（申请人提供）：细胞凋亡是一种细胞自杀过程，参与胚胎发育、癌症和自身免疫性疾病等多种生理和病理活动。细胞凋亡的诱导可以通过半胱天冬酶依赖性和独立过程介导。不依赖半胱天冬酶的细胞凋亡的机制尚未被充分了解。 AIF 是一种线粒体黄素蛋白，可触发不依赖于半胱天冬酶的细胞凋亡。我们克隆了一种新型 AIF 同源分子，命名为 AMID。 AMID 位于线粒体外膜。 AMID 的过度表达会诱导不依赖 caspase 的细胞凋亡。此外，AMID 是由肿瘤抑制因子 p53 诱导的，与单独匹配的正常组织相比，肿瘤中 AMID 的表达下调。我们假设 AMID 通过新机制诱导不依赖 caspase 的细胞凋亡，并且 AMID 是参与 p53 介导的下游效应的肿瘤抑制因子。为了检验我们的假设，我们提出了三个具体目标：1）。探讨AMID诱导的caspase非依赖性细胞凋亡的机制； 2）。研究AMID在p53介导的细胞凋亡和细胞生长停滞中的作用； 3）。利用体外细胞培养系统和小鼠体内基因敲除研究来确定 AMID 是否是肿瘤抑制基因。成功完成拟议的研究将有助于了解非 caspase 依赖性细胞凋亡的分子机制以及 AMID 在 p53 介导的生物效应和肿瘤发生中的作用。