PROTEIN PHOSPHATASE 1 (PP1) IN THE REGULATION OF MITOTIC EXIT AND NUCLEAR ORGANISATION

负责生物体成功繁殖和发育的重要信息被包装在细胞内，必须正确地传递给下一代细胞。这种传递信息的过程被称为细胞分裂，也被称为有丝分裂。在人类中，一个受精的单细胞卵需要多次细胞分裂才能形成一个新的个体。在成年人中，神经和肌肉细胞不分裂，但肝细胞每年分裂一次。骨髓中的血细胞前体和肠道细胞每天发生不止一次分裂。因此，我们的生存需要每天产生数百万个细胞。有丝分裂是任何细胞生命中的一个极其重要的阶段，它必须在没有错误的情况下进行。如果细胞分裂出错，那么对细胞或后代可能会产生重大后果。发育过程中的有丝分裂错误可能导致畸形或流产，在成年人中可能导致癌症。这项拟议中的研究正在研究调节有丝分裂最后步骤的蛋白质。蛋白质可以有非常特殊的功能。有些对构建结构很重要，而另一些则参与细胞内发生的化学反应。一类具有化学功能的蛋白质被称为磷酸酶，它们参与许多重要的细胞反应。蛋白磷酸酶1（PP 1）。我以前的研究表明，PP 1与伴侣蛋白Repo-Man一起对控制细胞分裂非常重要，它们的功能障碍会导致细胞后代出现严重问题。特别是，它们产生衍生细胞，这些衍生细胞在基因组物质和核板层（将基因组物质封闭在细胞中的重要屏障）的组织中表现出错误。这些缺陷与癌细胞和衰老过程中细胞中发生的缺陷相似。因此，我们必须更深入地了解PP 1是如何工作的，以及为什么它的功能障碍会影响细胞分裂的结果。该提案旨在更好地了解PP 1如何促进细胞分裂的调节，如果这个过程出错，对细胞的后果是什么，并确定对PP 1活性重要的新蛋白质。最后，获得这些分子如何一起工作的高度详细的描述将提供背景手段，以产生可以通过调节它们的作用而起作用的化学物质，因此可以用于控制病理情况下的细胞分裂。

The important information that is responsible for the successful reproduction and development of an organism is packaged within cells and must be passed on correctly to the next generation of cells. This passing on the information is referred to as cell division and is called mitosis. In humans, a fertilized single-celled egg requires many cell divisions to make a new individual. In an adult, nerve and muscle cells do not divide but liver cells divide once a year. More than one division a day occurs in blood cell precursors in the bone marrow and in the cells lining the gut. Therefore our survival requires a production of millions of cells daily. Mitosis is an extremely important phase in the life of any cell and it must be carried out without errors. If a cell division goes wrong then major consequences may arise either for the cell or for future generations. Mitotic errors during development can produce malformations or miscarriages and, in adults they can lead to cancer. The proposed research is looking at the proteins that regulate the final steps of mitotic divisions. Proteins can have extremely specialised functions. Some are important for building structures while others are involved in chemical reactions occurring within a cell. One family of such proteins with chemical functions is called phosphatases and they are involved in many important cell reactions. Among them is Protein phosphatase 1 (PP1). My previous research has shown that PP1 together with a partner protein Repo-Man is very important for controlling cell division and their malfunction leads to dramatic problems in the cell progeny. In particular, they produce derivative cells that manifest mistakes in the organization of the genomic material and the Nuclear Lamina (an important barrier that enclose the genomic material in a cell). These defects are similar to the ones that occur in cancer cells and in cells during the aging process. It is therefore imperative to acquire more in depth knowledge on how PP1 works and why its malfunction affects the outcome of cell division. The proposal is to gain a better understanding of how this PP1 contributes to the regulation of cell division, what are the consequences to the cell should this process go wrong and also to identify new proteins that are important for PP1 activity. Finally, obtaining a highly detailed description of how these molecules work together will provide the background mean to generate chemicals that can act by modulating their action and therefore could be used to control cell division in pathological cases.