Mitotic exit control

有丝分裂退出控制

• 批准号: 9265105
• 负责人: ANGELIKA B AMON
• 金额: $ 31.37万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265105
• 关键词: Address; Alpha Cell; Anaphase; Animals; Binding; Cell Cycle; Cell Cycle Regulation; Cell Cycle Stage; Cell Death; Cell Nucleus; Cell Proliferation; Cells; Centrosome; Chromosome Segregation; Chromosomes; Complement; Cues; Defect; Development; Disease; Down-Regulation; Drosophila polo protein; Ensure; Event; GTPase-Activating Proteins; Genome; Growth; Growth and Development function; Guanosine Triphosphate Phosphohydrolases; In Vitro; Lead; Malignant Neoplasms; Mammals; Metaphase; Microtubules; Mitosis; Mitotic; Mitotic Activity; Mitotic spindle; Modeling; Molecular; Mothers; Neck; Normal Cell; Nuclear; Nuclear Envelope; Organ Size; Organism; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Positioning Attribute; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Recruitment Activity; Regulation; Saccharomyces cerevisiae; Saccharomycetales; Scaffolding Protein; Signal Pathway; Signal Transduction; Specificity; Testing; Work; Yeasts; cell growth; daughter cell; event cycle; experimental study; in vivo; prevent; protein complex; public health relevance; response; spindle pole body

 DESCRIPTION (provided by applicant): In budding yeast, the final cell cycle transition, exit from mitosis, is governed by the Mitotic Exit Network (MEN), a GTPase signaling cascade. The homologous pathway in mammals is known as the Hippo/Lats pathway, a major regulator of organ size and organismal growth in animals. Our recent work led to the exciting finding that multiple signals control the activity of the Mitotic Exit Network and that MEN regulation does not solely occur through the GTPase switch but that the GTPase effector kinase also receives and integrates regulatory signals. In Specific Aim 1 we will determine how a spatial signal, spindle position controls MEN activity and hence exit from mitosis. In Specific Aim 2 we will investigate how a temporal signal, anaphase entry, ensures that the MEN is only active during the final stages of the cell cycle. Finally, in Specific Aim 3 we will investigate how other GTPase signaling components function as signal recipients. We will study how the GTPase effector kinase integrates signals from the MEN GTPase and the Polo kinase Cdc5. The experiments proposed here will significantly contribute to our understanding of cell cycle control and how the order of events of the cell cycle are established, a cell cycle feature often lost during abnormal development and diseases such as cancer. They will uncover the molecular mechanisms that ensure that exit from mitosis only occurs after chromosomes have been segregated and each daughter cell has received a complete complement of the genome. Our studies will also have a significant impact on the GTPase signaling field. Our work on a GTPase pathway that governs exit from mitosis led to the realization that GTPase signaling pathways are not only regulated at the level of the GTPase switch but at subsequent signaling step. Understanding how GTPase effector kinases serve as signal recipients is a still poorly understood aspect of GTPase signaling. GTPase signaling pathways are central regulators of cell growth and proliferation and development. Understanding GTPase signaling at the molecular level is thus vital for understanding the principles underlying normal cell growth proliferation and abnormal development and disease states.

 描述（由适用提供）：在萌芽的酵母中，最终的细胞周期过渡（从有丝分裂中退出）受丝分裂出口网络（MEN）（GTPase信号级联）的控制。哺乳动物的同源途径被称为河马/LATS途径，这是动物器官大小和有机生长的主要调节剂。我们最近的工作导致了令人兴奋的发现，即多个信号控制有丝分裂出口网络的活动，而男性调节不仅是通过GTPase开关进行的，但是GTPase效应激酶也会接收并集成调节信号。在特定目标1中，我们将确定空间信号如何控制男性活动，从而退出有丝分裂。在特定目标2中，我们将研究临时信号，后期进入如何确保男性仅在细胞周期的最后阶段处于活跃。最后，在特定目标3中，我们将研究其他GTPase信号成分如何充当信号受体。我们将研究GTPase效应子激酶如何整合MEN GTPase和Polo激酶CDC5的信号。这里提出的实验将显着有助于我们对细胞周期控制的理解以及如何建立细胞周期的顺序，在异常发育过程中经常丢失的细胞周期特征以及诸如癌症之类的疾病。他们将发现仅在隔离染色体后才发生有丝分裂的分子机制，并且每个子细胞都已完成基因组的完整完成。我们的研究还将对GTPase信号传导场产生重大影响。我们在控制有丝分裂的GTPase途径上的工作导致人们意识到，GTPase信号通路不仅在GTPase开关的水平下受到调节，而且在随后的信号传导步骤下进行了调节。了解GTPase效应子激酶如何用作信号受体是GTPase信号传导的一个方面仍然很少的。 GTPase信号通路是细胞生长，增殖和发育的中心调节剂。因此，了解分子水平的GTPase信号传导对于理解正常细胞生长增殖和异常发育和疾病状态的原理至关重要。