AMID in Apoptosis and p53-Mediated Downstream Effects

描述（由申请人提供）：细胞凋亡是一种细胞自杀过程，涉及多种生理和病理活动，如胚胎发育、癌症和自身免疫性疾病。凋亡的诱导可以通过caspase依赖性和独立过程介导。caspase非依赖性细胞凋亡的机制尚未得到很好的理解。AIF是一种线粒体黄素蛋白，可触发caspase非依赖性细胞凋亡。我们克隆了一个新的AIF同源分子，命名为AMID。AMID定位于线粒体外膜。过表达AMID诱导caspase非依赖性细胞凋亡。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，AMID在肿瘤中的表达下调。我们假设AMID通过新机制诱导caspase不依赖的细胞凋亡，并且AMID是一种参与p53介导的下游效应的肿瘤抑制因子。为了验证我们的假设，我们提出了三个具体目标：1)。探讨amide诱导caspase非依赖性细胞凋亡的机制；2)。探讨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确定AMID是否为肿瘤抑制基因。这些研究的成功完成将有助于了解caspase非依赖性细胞凋亡的分子机制，以及AMID在p53介导的生物学效应和肿瘤发生中的作用。

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.