Analysis of Cell Death Regulation in C. elegans

线虫细胞死亡调控分析

• 批准号: 8267813
• 负责人: BARBARA CONRADT
• 金额: $ 11.48万
• 依托单位: LUDWIG MAXIMILIAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267813
• 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; public health relevance; snail protein; transcription factor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: ECT 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.

描述(申请人提供)：不对称细胞分裂产生不同命运的子代细胞，这对细胞多样性的产生至关重要。程序性细胞死亡或凋亡消除了多余的细胞，这对细胞稳态至关重要。细胞不对称分裂和细胞凋亡通常在功能上是联系在一起的。例如，众所周知，不对称分裂的干细胞可以控制其子代的凋亡命运。然而，到目前为止，连接这两个基本过程的分子和机制仍然难以捉摸。我们的长期目标是充分了解细胞不对称分裂如何控制细胞凋亡。为此，我们使用线虫秀丽线虫作为模型系统。线虫的NSM神经母细胞不对称地分裂，产生一个较大的细胞，NSM，它存活下来，以及一个较小的细胞，NSM姐妹细胞，经历凋亡。细胞分裂后不久，编码促凋亡蛋白BH3的EGL-1基因在较小的NSM姐妹细胞中转录激活，但在较大的NSM姐妹细胞中不被激活，从而导致特异性地在NSM姐妹细胞中诱导凋亡。在之前的资助阶段，我们确定了导致EGL-1转录不对称的分子机制。我们发现，正是由于NSM姐妹细胞中没有Snail相关的转录抑制因子CES-1，以及细胞分裂后立即在NSM中存在CES-1，才导致了EGL-1在NSM姐妹细胞中的特异性转录。我们还发现了一个三组分的通路，dnj-11/MIDA1，CES-2/HLF，CES-1/Snail通路，这是NSM神经母细胞不对称分裂和将CES-1蛋白排除在NSM姐妹细胞之外所必需的。目前应用的总体目标是阐明dnj-11/MIDA1、CES-2/HLF、CES-1/Snail通路协调调节NSM神经母细胞极性、不对称NSM神经母细胞分裂以及CES-1蛋白对NSM的限制的分子机制。细胞凋亡是一个进化保守的过程，在胚胎发育和胚胎后维持细胞动态平衡方面发挥着重要作用。它的解除调控与人类的多种疾病有关，最明显的是各种类型的癌症、自身免疫性疾病和神经退行性疾病；然而，到目前为止，人们对细胞凋亡的正常控制知之甚少。我们发现细胞的不对称分裂可以直接控制细胞的凋亡，这代表了细胞凋亡调控的一个新概念。因此，拟议的研究将有助于我们对发育健康障碍的基本理解，并与理解癌症干细胞的行为特别相关，从而有助于肿瘤的发生。公共卫生相关性：ECT细胞凋亡是一个进化保守的过程，在胚胎发育和胚胎后维持细胞内稳态方面发挥重要作用。它的解除调控与人类的多种疾病有关，最明显的是各种类型的癌症、自身免疫性疾病和神经退行性疾病；然而，到目前为止，人们对细胞凋亡的正常控制知之甚少。我们发现细胞的不对称分裂可以直接控制细胞的凋亡，这代表了细胞凋亡调控的一个新概念。因此，拟议的研究将有助于我们对发育健康障碍的基本理解，并与理解癌症干细胞的行为特别相关，从而有助于肿瘤的发生。