Mitotic exit control

 描述(申请人提供)：在萌芽酵母中，最终的细胞周期转变，即退出有丝分裂，是由有丝分裂出口网络(MEN)控制的，这是一个GTPase信号级联反应。哺乳动物中的同源途径被称为河马/LATS途径，它是动物器官大小和组织生长的主要调节因子。我们最近的工作导致了令人兴奋的发现，多个信号控制有丝分裂退出网络的活性，并且MAN的调节不仅通过GTP酶开关发生，而且GTP酶效应蛋白激酶也接收和整合调节信号。在特定的目标1中，我们将确定空间信号，纺锤体的位置如何控制男性的活动，从而退出有丝分裂。在特定的目标2中，我们将研究时间信号，即后期进入，如何确保男性仅在细胞周期的最后阶段活跃。最后，在特定的目标3中，我们将研究其他GTPase信号组件如何作为信号受体发挥作用。我们将研究GTP酶效应激酶如何整合来自MEN GTP酶和Polo激酶CDC5的信号。这里提出的实验将大大有助于我们理解细胞周期控制以及细胞周期事件的顺序是如何建立的，这是一个在异常发育和癌症等疾病中经常丢失的细胞周期特征。他们将揭示确保退出有丝分裂的分子机制，只有在染色体被分离并且每个子细胞都收到了完整的基因组后才会退出。我们的研究也将对GTPase信号领域产生重大影响。我们在控制有丝分裂退出的GTPase途径方面的工作使我们认识到，GTPase信号通路不仅在GTPase开关水平上受到调节，而且在随后的信号步骤中受到调节。了解GTPase效应蛋白激酶如何作为信号受体仍然是GTPase信号转导的一个鲜为人知的方面。GTPase信号通路是细胞生长、增殖和发育的中心调节因子。因此，在分子水平上理解GTPase信号对于理解细胞正常生长、增殖、异常发育和疾病状态的原理至关重要。

 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.