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

基本信息

批准号：
7408606
负责人：
Philippa C. Marrack
金额：
$ 26.52万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-14 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7408606
关键词：
Apoptosis Apoptotic Autoimmune Diseases Biological Caspase Cell Culture System Cells Doctor of Philosophy Ectopic Expression Embryo Embryonic Development Family member Fibroblasts Flavoproteins Gene Expression Genes Goals Growth HRAS gene Homologous Protein In Vitro Induction of Apoptosis Kinetics Knock-out Localized Malignant Neoplasms Mediating Membrane Mitochondria Molecular Mus Mutation Normal tissue morphology Pathway interactions Personal Satisfaction Physiological Primary Neoplasm Process Protein Overexpression Protein p53 Proteins Rattus Regulation Role Screening procedure System TP53 gene Testing Tumor Suppressor Genes Tumor Suppressor Proteins cancer cell cell growth cell suicide cytochrome c endonuclease G gene function human AMID protein in vivo malignant phenotype novel promoter tumor tumorigenesis yeast protein yeast two hybrid system

项目摘要

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（由申请人提供）：凋亡是参与各种生理和病理活性的细胞自杀过程，例如胚胎发育，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。尚未充分了解胱天蛋白酶非依赖性凋亡的机制。 AIF是一种线粒体黄蛋蛋白，可触发与caspase无关的凋亡。我们克隆了一个新型的AIF同源分子，称为AM的。中间位于线粒体的外膜。在诱导caspase非依赖性细胞凋亡中的过表达。此外，与单独匹配的正常组织相比，肿瘤抑制剂p53诱导了肿瘤p53。我们假设通过新机制诱导胱天蛋白酶非依赖性凋亡，而在肿瘤抑制剂中涉及p53介导的下游效应。为了检验我们的假设，我们提出了三个具体目标：1）。研究在诱发的caspase非依赖性凋亡中的机制； 2）。研究在p53介导的细胞凋亡和细胞生长停滞中的作用； 3）。确定使用体外细胞培养系统和小鼠体内基因敲除研究是否是肿瘤抑制基因。成功完成拟议的研究将有助于理解caspase非依赖性凋亡的分子机制以及在p53介导的生物学作用和肿瘤发生中的作用。