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ELONGIN C: FUNCTION AND ROLE IN VHL DISEASE

ELONGIN C：在 VHL 疾病中的功能和作用

基本信息

批准号：
6342203
负责人：
Linda E Hyman
金额：
$ 14.85万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-18 至 2003-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6342203
关键词：
Von Hippel Lindau syndrome enzyme activity gene expression oxidative stress protein binding protein protein interaction protein structure function transcription factor tumor suppressor proteins yeasts

项目摘要

Several lines of evidence indicate that Elongin C, a regulatory subunit of the Elongin transcription factor, plays an essential role, unrelated to transcription, in the tumor suppression function of the von Hippel-Landau protein (VHL). The overall objective of this proposal is to determine the biological function(s) of Elongin C and its role in VHL tumor suppression. We have identified the yeast homologue of Elongin C. Our rationale is that Elongin C function will be conserved in mammalian cells. Our preliminary data indicate that yeast Elongin C interacts strongly and specifically with 4 yeast proteins: Snf4, Yap4, Yap6 and Mdj1. Notably each of these Elongin C binding partners has a mammalian homologue and can be linked to specific stress responses. Thus our hypothesis is that Elongin C is a key protein in the stress response. This hypothesis will be examined as described in the following specific aims. Specific Aim 1. To characterize yeast Elongin C during the stress response. Preliminary studies indicate that the yeast Elongin C gene is non-essential, expressed at low levels during normal cell growth and that the protein is present in both the nucleus and in the cytoplasm. Experiments are described to assess the effects of hypoxic, nutrient, and oxidant stress in Elongin c null strains. Specific Aim 2. To examine the nature and significance of the Elongin C interactions with Snf4, Yap4, Yap6 and Mdj1. Snf4 is the homologue of the gamma subunit of mammalian AMP-activated protein kinase (AMPK). The affect of binding of Elongin C to Snf4 on the kinase activity will be assessed. Yap4 and Yap6 are putative transcription factors and Mdj1 is a mitochondrial chaperone. The interaction between these proteins and Elongin C will identify other factors that may operate in parallel or be redundant with Elongin C. A synthetic lethal screen is described to identify other factors that may compensate for absence of Elongin C VHL tumor suppression, the elucidation of the function(s) of Elongin C may lead to the identification of new therapeutic targets for treatment of VHL disease.

几条证据表明，延伸蛋白C，延伸蛋白转录因子的调节亚基，在von Hippel-Landau蛋白（VHL）的肿瘤抑制功能中发挥重要作用，与转录无关。本提案的总体目标是确定Elongin C的生物学功能及其在VHL肿瘤抑制中的作用。我们已经鉴定了延伸蛋白C的酵母同源物。我们的理由是，在哺乳动物细胞中，延伸蛋白C的功能是保守的。我们的初步数据表明，酵母延伸蛋白C与4种酵母蛋白质：Snf 4，Yap 4，Yap 6和Mdj 1强烈而特异地相互作用。值得注意的是，这些延伸蛋白C结合配偶体中的每一个都具有哺乳动物同源物，并且可以与特定的应激反应相关联。因此，我们的假设是，延伸蛋白C是应激反应中的关键蛋白。将按照以下具体目标对这一假设进行审查。具体目标1。研究酵母Elongin C在应激反应中的特性。初步研究表明，酵母延伸蛋白C基因是非必需的，在正常细胞生长期间以低水平表达，并且该蛋白质存在于细胞核和细胞质中。描述了评估低氧、营养和氧化应激对Elongin c无效菌株的影响的实验。具体目标2。研究Elongin C与Snf 4、Yap 4、Yap 6和Mdj 1相互作用的性质和意义。Snf 4是哺乳动物AMP活化蛋白激酶（AMPK）γ亚基的同源物。将评估延伸蛋白C与Snf 4结合对激酶活性的影响。Yap 4和Yap 6是推定的转录因子，Mdj 1是线粒体伴侣。这些蛋白质与延伸蛋白C之间的相互作用将鉴定出可能与延伸蛋白C平行或冗余的其他因子。描述了一种合成致死筛选以鉴定可补偿Elongin C VHL肿瘤抑制的缺乏的其他因子，Elongin C的功能的阐明可导致鉴定用于治疗VHL疾病的新治疗靶点。