Control of the cell cycle by mRNA degradation

通过 mRNA 降解控制细胞周期

• 批准号: 8016705
• 负责人: MARK E SCHMITT
• 金额: $ 30.01万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016705
• 关键词: Anemia; Antineoplastic Agents; Appearance; Biochemical; Biological; Biological Models; Cancer Control; Cartilage; Cell Cycle; Cell Cycle Regulation; Cell division; Cell physiology; Cells; Cellular biology; Collaborations; Complex; Data; Development; Disease; Endoribonucleases; Enzymes; Eukaryota; Failure; Genetic; Genetic Models; Growth; Hair; Human; Immunologic Deficiency Syndromes; Inborn Genetic Diseases; Lead; Learning; Location; Lymphoma; Malignant Neoplasms; Messenger RNA; Metabolism; MicroRNAs; Molecular; Molecular Analysis; Multienzyme Complexes; Mutation; Organelles; Pathogenesis; Phenotype; Play; Predisposition; Process; Proteins; RNA; Recording of previous events; Regulation; Ribonucleases; Ribonucleoproteins; Risk; Role; Saccharomyces cerevisiae; Staging; Structure; System; Testing; Time; Work; Yeasts; base; design; disease phenotype; endoribonuclease; human disease; insight; mRNA Transcript Degradation; mutant; public health relevance; research study

DESCRIPTION (provided by applicant): Title: Control of the cell cycle by mRNA degradation. Over the last period of this project we have extensively defined the role of the ribonucleoprotein endoribonuclease, RNase MRP, in mRNA degradation and cell cycle control. These studies have led us to discovering a new organelle, the TAM (Temporal Asymmetric MRP) body. We have found that this structure is P (processing) body "like". But in contrast to P bodies that are found throughout cells and the cell cycle, TAM bodies are temporally and spatially assembled organelles whose function is to degrade specific mRNAs at a discrete time and location in the cell cycle. P bodies or GW bodies have been implicated in regulating development, microRNAs and the cell cycle. RNase MRP is conserved throughout eukaryotes and mutations in the human RNA component have implicated this enzyme as an essential growth regulator. Human mutations cause Cartilage Hair Hypoplasia (CHH) a recessively inherited disorder characterized by short stature, brittle hair, anemia, immunodeficiency, and a predisposition to the development of lymphomas and other cancers. Data from our lab in collaboration with others has shown that human RNase MRP is also playing a role in destabilizing certain mRNAs. Failure to normally degrade certain mRNAs could easily cause the cell cycle delay seen in the human disease and the resulting phenotypes. Hence, these studies will have direct implications on human disease and pathogenesis. Experimentation will attack this problem in the yeast, Saccharomyces cerevisiae, an excellent RNase MRP model system that has proven to be highly conserved with the mammalian model systems. The specific aims have been designed to take advantages of the strengths in the yeast systems allowing us to learn more about RNase MRP, TAM bodies, and mRNA degradation. Our past history of using a simple genetic model system to lend insights into human disease considerably strengthens our proposal. In addition, our analysis of the molecular mechanism whereby complex genetic interactions lead to a phenotype and disease will provide much needed information as to how disease occurs in humans. PUBLIC HEALTH RELEVANCE: RNase MRP is conserved throughout eukaryotes and mutations in the human RNA component have implicated this enzyme as an essential growth regulator. Human mutations lead to Cartilage Hair Hypoplasia (CHH), a recessively inherited disorder characterized by short stature, brittle hair, anemia, immunodeficiency, and a predisposition to the development of lymphomas and other cancers. Based on our results from yeast it has already been shown that human RNase MRP is also playing a role in destabilizing certain mRNAs. This is data from our lab in collaboration with others. Failure to normally degrade certain mRNAs could easily cause the cell cycle delay seen in the human disease and the resulting phenotypes. Hence, these studies will have direct implications on human disease and pathogenesis. Over the last several years an immense amount has been learned about how cells control their division process. However the details and exact mechanism of many of the steps in the regulation of this process are still poorly understood. The incorrect regulation of cell division is the basis of all cancers. Understanding the details of how cell division is regulated and controlled is essential for controlling cancer and finding cures. RNase MRP is directly involved in the late stages of the cell division cycle by regulating mRNA levels of critical cell cycle molecules. The project will provide us with a better picture of how cells regulate the cell cycle and may provide some important new targets for antineoplastic agents.

描述（由申请方提供）：标题：通过mRNA降解控制细胞周期。在这个项目的最后一段时间里，我们已经广泛地定义了核糖核蛋白核糖核酸内切酶（RNase MRP）在mRNA降解和细胞周期控制中的作用。这些研究使我们发现了一种新的细胞器，TAM（时间不对称MRP）体。我们已经发现，这种结构是P（加工）体的“类”。但与在整个细胞和细胞周期中发现的P体相反，TAM体是时间和空间组装的细胞器，其功能是在细胞周期中的离散时间和位置降解特定的mRNA。P体或GW体参与调节发育、microRNA和细胞周期。 RNase MRP在整个真核生物中是保守的，并且人类RNA组分中的突变已经暗示这种酶是必需的生长调节剂。人类基因突变导致毛囊发育不全（CHH），这是一种复发性遗传性疾病，其特征是身材矮小、头发脆、贫血、免疫缺陷以及易患淋巴瘤和其他癌症。我们实验室与其他人合作的数据表明，人类RNase MRP也在破坏某些mRNA的稳定中发挥作用。不能正常降解某些mRNA很容易导致人类疾病中观察到的细胞周期延迟和由此产生的表型。因此，这些研究将对人类疾病和发病机制产生直接影响。 实验将解决这个问题，在酵母，酿酒酵母，一个优秀的RNase MRP模型系统，已被证明是高度保守的哺乳动物模型系统。具体的目标是利用酵母系统的优势，使我们能够更多地了解RNase MRP，TAM体和mRNA降解。我们过去使用简单的遗传模型系统来深入了解人类疾病的历史大大加强了我们的建议。此外，我们对复杂的遗传相互作用导致表型和疾病的分子机制的分析将提供关于疾病如何在人类中发生的急需的信息。 公共卫生相关性：RNase MRP在整个真核生物中是保守的，并且人类RNA组分中的突变已经暗示这种酶是必需的生长调节剂。人类基因突变导致毛囊发育不全（CHH），这是一种复发性遗传性疾病，其特征是身材矮小、头发脆、贫血、免疫缺陷以及易患淋巴瘤和其他癌症。基于我们对酵母的研究结果，已经表明人类RNase MRP也在使某些mRNA不稳定中发挥作用。这是我们实验室与其他人合作的数据。不能正常降解某些mRNA很容易导致人类疾病中观察到的细胞周期延迟和由此产生的表型。因此，这些研究将对人类疾病和发病机制产生直接影响。 在过去的几年里，人们对细胞如何控制其分裂过程有了大量的了解。然而，对这一过程的许多调节步骤的细节和确切机制仍然知之甚少。细胞分裂的不正确调节是所有癌症的基础。了解细胞分裂是如何调节和控制的细节对于控制癌症和寻找治疗方法至关重要。RNase MRP通过调节关键细胞周期分子的mRNA水平直接参与细胞分裂周期的晚期阶段。该项目将为我们更好地了解细胞如何调节细胞周期提供帮助，并可能为抗肿瘤药物提供一些重要的新靶点。