Analysis of Cell Death Regulation in C. elegans

线虫细胞死亡调控分析

• 批准号: 8011154
• 负责人: BARBARA CONRADT
• 金额: $ 15.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-12 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011154
• 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

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.

项目总结 不对称的细胞分裂产生了不同命运的子细胞，这对 细胞多样性的产生。程序性细胞死亡或凋亡消除了多余的 细胞，这对细胞动态平衡是至关重要的。不对称的细胞分裂和凋亡是 通常在功能上联系在一起。例如，众所周知，不对称分裂干细胞 可以控制他们女儿的死亡命运。然而，分子和机制 到目前为止，将这两个基本过程结合在一起的过程一直难以捉摸。我们的长期计划 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 正在使用线虫秀丽线虫作为模型系统。 线虫的NSM神经母细胞不对称分裂，形成一个更大的细胞，即 NSM存活，以及一个较小的细胞，NSM姐妹细胞，经历细胞凋亡。很快就会 在细胞分裂后，编码促凋亡BH3蛋白的EGL-1基因是 在较小的NSM姐妹细胞中转录激活，但不在较大的NSM中转录激活，从而 在NSM姊妹细胞中特异性地诱导细胞凋亡。在上一次筹资期间， 我们确定了导致EGL-1不对称转录的分子机制。我们发现 这是因为NSM姐妹中缺少与蜗牛相关的转录抑制因子CES-1 细胞分裂后立即出现的细胞及其在NSM中的存在导致EGL-1转录 特别是在NSM的姐妹细胞中。我们还确定了一条三组分的途径，dnj- 11/MIDA1，Ces-2/HLF，Ces-1/Snail途径，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。整体而言 目前应用的目的是描述dnj-dnj-1的分子机制。 11/MIDA1、CES-2/HLF、CES-1/Snail途径协同调节NSM神经母细胞极性， NSM神经母细胞分裂不对称以及CES-1蛋白对NSM的限制。 细胞凋亡是一种进化保守的过程，在胚胎发育过程中发挥着重要作用。 在胚胎发育和胚胎后维持细胞的动态平衡。它的放松管制 与人类的多种疾病有关，最明显的是各种癌症， 自身免疫性疾病和神经退行性疾病；然而，到目前为止，人们知之甚少 正常情况下细胞凋亡是如何控制的。我们发现，细胞凋亡可以直接通过 由细胞不对称分裂控制，代表了细胞凋亡调控的新概念。 因此，提出的研究将有助于我们对发展的基本理解 并与理解癌症干细胞的行为特别相关 因此，也就是肿瘤发生。