Tyrosine kinases and phosphatases in cell cycle checkpoint responses

为了使生物体生长和发育，构成组织和器官的细胞需要经历细胞分裂的过程，其中单个细胞生长，然后分裂成两个细胞。在细胞生长和分裂的过程中，整个基因组需要复制（这发生在S期），然后平均分为两个子细胞。在S阶段，存在几个所谓的“检查点”机制，以确保这以有序和精确的方式发生。所谓的“DNA复制检查点”延迟S期进展，以应对可能导致DNA损伤的“复制压力”。蛋白酪氨酸激酶（PTK）在许多人类实体瘤和血液恶性肿瘤中过度活化，导致肿瘤进展的各个方面。我们的初步研究表明，蛋白酪氨酸磷酸酶的PTKs的失活可能是必不可少的S期进展的抑制复制应激反应。我们的目标是了解PTKs和酪氨酸磷酸酶对S期检查点的分子机制。我们的研究将为哺乳动物中DNA复制应激诱导的检查点反应提供重要的见解，并确定过度激活的PTKs可能有助于肿瘤发展的前所未有的机制。

In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a process of cellular division, wherein individual cells grow and then divide into two cells. During this process of cellular growth and division the entire genome needs to be duplicated (this occurs during S-phase) and then divided equally into the two daughter cells. In S-phase several so-called 'checkpoint' mechanisms exist which ensure that this occurs in an orderly and precise manner. The so-called 'DNA replication checkpoint' delays S-phase progression in response to 'replication stresses' that may otherwise cause DNA damage. Protein tyrosine kinases (PTKs) are hyperactivated in many human solid tumours and blood malignancies contributing to varied aspects of tumour progression. Our preliminary studies indicate that the inactivation of PTKs by protein tyrosine phosphatases may be essential for the suppression of S-phase progression in response to replication stress. Our goal is to understand the molecular mechanisms by which PTKs and tyrosine phosphatases contribute to S-phase checkpoints. Our studies will provide important insights into DNA replication stress-induced checkpoint responses in mammals and identify unprecedented mechanisms by which hyperactivated PTKs may contribute to tumour development.