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Analysis of Cell Death Regulation in C. elegans

线虫细胞死亡调控分析

基本信息

批准号：
8204968
负责人：
BARBARA CONRADT
金额：
$ 14.41万
依托单位：
LUDWIG MAXIMILIAN UNIVERSITY
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：
2004-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204968
关键词：
Adaptor Signaling Protein Affect Apoptosis Apoptotic Autoimmune Diseases Behavior Biological Models Caenorhabditis elegans Cell Death Cell division Cells Cessation of life Coupled Coupling Data Daughter Development Disease Embryonic Development Ensure Exclusion Funding Generations Genes Genetic Genetic Screening Genetic Transcription Glycogen Synthase Kinase 3 Goals Health Homeostasis Human Induction of Apoptosis Link Maintenance Mediating Molecular Molecular Chaperones Nematoda Neurodegenerative Disorders Neurons Pathway interactions Phosphotransferases Play Process Proteins Regulation Role Sister Snails Stem cells Testing Transcription Repressor/Corepressor Transcriptional Regulation Ubiquitin-Protein Ligase Complexes Work base cancer stem cell cancer type daughter cell neuroblast prevent snail protein transcription factor tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Asymmetric cell division creates daughter cells of different fates, and this is critical for the generation of cellular diversity. Programmed cell death or apoptosis eliminates superfluous cells, and this is critical for cellular homeostasis. Asymmetric cell division and apoptosis are often functionally linked. For example, it is well known that asymmetrically dividing stem cells can control the apoptotic fate of their daughters. However, the molecules and mechanisms involved in coupling these two fundamental processes have so far been elusive. Our long term goal is to understand fully how asymmetric cell division can control apoptosis. To that end we are using the nematode Caenorhabditis elegans as a model system. The NSM neuroblast of C. elegans divides asymmetrically to give rise to a larger cell, the NSM, which survives, and a smaller cell, the NSM sister cell, which undergoes apoptosis. Shortly after cell division, the gene egl-1, which encodes a pro-apoptotic BH3-only protein, is transcriptionally activated in the smaller NSM sister cell, but not the larger NSM, thereby causing apoptosis induction specifically in the NSM sister cell. In the previous funding period, we identified the molecular mechanism that leads to asymmetric egl-1 transcription. We found that it is the absence of the Snail-related transcriptional repressor CES-1 from the NSM sister cell and its presence in the NSM immediately after cell division that causes egl-1 transcription specifically in the NSM sister cell. We have also identified a three component pathway, the dnj- 11/MIDA1, ces-2/HLF, ces-1/Snail pathway, which is required for the asymmetric division of the NSM neuroblast and the exclusion of the CES-1 protein from the NSM sister cell. The overall objective of the current application is to delineate the molecular mechanisms by which the dnj- 11/MIDA1, ces-2/HLF, ces-1/Snail pathway coordinately regulates NSM neuroblast polarity, asymmetric NSM neuroblast division, and the restriction of CES-1 protein to the NSM. Apoptosis is an evolutionary conserved process that plays important roles during embryonic development and in the postembryonic maintenance of cellular homeostasis. Its deregulation has been implicated in a variety of diseases in humans most notably various types of cancers, autoimmune disorders and neurodegenerative diseases; however very little is known thus far about how apoptosis is normally controlled. We discovered that apoptosis can directly be controlled by asymmetric cell division, which represents a new concept in apoptosis regulation. Therefore, the proposed studies will contribute to our basic understanding of developmental health disorders and are specifically relevant to understanding the behavior of cancer stem cells and, hence, tumorigenesis.

项目概要不对称细胞分裂产生不同命运的子细胞，这对于细胞多样性的产生。程序性细胞死亡或细胞凋亡消除了多余的细胞细胞，这对于细胞稳态至关重要。细胞不对称分裂和凋亡是通常在功能上联系在一起。例如，众所周知，不对称分裂的干细胞可以控制其女儿的凋亡命运。然而，分子和机制迄今为止，这两个基本过程的耦合仍然难以捉摸。我们的长期目标是充分了解不对称细胞分裂如何控制细胞凋亡。为此我们使用线虫秀丽隐杆线虫作为模型系统。线虫的 NSM 神经母细胞不对称分裂，产生更大的细胞，即 NSM 存活下来，而一个较小的细胞，即 NSM 姐妹细胞，则经历细胞凋亡。不久细胞分裂后，基因egl-1编码促凋亡的BH3蛋白，在较小的 NSM 姐妹细胞中转录被激活，但在较大的 NSM 中则不然，因此特别是在 NSM 姐妹细胞中引起细胞凋亡诱导。在上一个资助期内，我们确定了导致不对称egl-1转录的分子机制。我们发现 NSM 姐妹中缺少 Snail 相关转录抑制因子 CES-1 细胞及其在细胞分裂后立即出现在 NSM 中，导致 egl-1 转录特别是在 NSM 姐妹细胞中。我们还确定了一个三成分途径，dnj- 11/MIDA1、ces-2/HLF、ces-1/Snail 通路，这是不对称分裂所必需的 NSM 神经母细胞和从 NSM 姐妹细胞中排除 CES-1 蛋白。整体当前应用的目的是描述 dnj-的分子机制 11/MIDA1、ces-2/HLF、ces-1/Snail 通路协调调节 NSM 神经母细胞极性， NSM 神经母细胞不对称分裂，以及 CES-1 蛋白对 NSM 的限制。细胞凋亡是一个进化保守过程，在胚胎发育过程中发挥着重要作用发育和细胞稳态的胚胎后维持。它的放松管制与人类的多种疾病有关，尤其是各种类型的癌症，自身免疫性疾病和神经退行性疾病；然而迄今为止我们知之甚少关于细胞凋亡通常是如何控制的。我们发现细胞凋亡可以直接由不对称细胞分裂控制，代表了细胞凋亡调控的新概念。因此，所提出的研究将有助于我们对发育的基本理解健康障碍，与了解癌症干细胞的行为特别相关以及肿瘤的发生。