Analysis of the regulation and function of the mitotic kinase Citron kinase in cell division

细胞是包括人类在内的许多生物的组成部分。所有这些生物的生长、发育和繁殖都依赖于精确而迷人的细胞分裂过程，这一过程忠实地将遗传信息在两个正在分裂的细胞之间分割开来。正确的细胞分裂也是决定细胞命运和组织结构的关键。这个过程中的错误导致了许多遗传疾病，包括唐氏综合症、小头畸形、不孕症和癌症。因此，彻底了解控制细胞分裂的机制可能会导致这些遗传疾病的新治疗方法的发展。此外，最近的证据还表明，细胞分裂与衰老之间存在明确的联系，因此，了解细胞分裂过程有助于了解衰老的自然过程和与衰老有关的早期疾病的起源。为了确保细胞分裂的保真度和稳健性，复杂的控制和监视机制已经发展起来。遗传物质——DNA——在细胞分裂时被压缩成染色体，无法产生新的因子。因此，控制细胞分裂的机制在很大程度上依赖于对细胞开始分裂前产生的蛋白质的功能和活性的调节。在控制细胞分裂的准确性和保真度方面起关键作用的一类蛋白质是丝氨酸/苏氨酸激酶。这些激酶可以通过添加磷酸基团（一种被称为磷酸化的过程）来调节许多其他细胞分裂蛋白（即底物）的功能、动力学和活性，从而改变其靶蛋白的机械和结构特性。这个项目的目标是剖析这种激酶之一的作用，香橼激酶（Citron kinase, CIT-K），它控制着细胞分裂的不同方面。我们建议使用尖端的后基因组技术来鉴定细胞分裂过程中CIT-K的所有底物，并了解CIT-K如何通过其他激酶的磷酸化来调节自身。由于CIT-K与人类原发性小头畸形有关，并被认为是抗癌治疗的潜在靶点，我们的研究不仅有助于了解控制细胞分裂和增殖的关键机制，还将为未来治疗这些人类疾病的疗法的发展奠定基础。

Cells are the building blocks of many organisms, including humans. Growth, development and reproduction in all these organisms depend on the accurate and fascinating process of cell division, which faithfully partitions the genetic information between the two dividing cells. Proper cell division is also crucial for determining cell fate and tissue organization. Errors during this process are responsible for many genetic diseases, including Down's syndrome, microcephaly, sterility, and cancer. Thus, a thorough understanding of the mechanisms that control cell division may lead to the development of novel therapeutic treatments for these genetic diseases. Moreover, recent evidence also indicates a clear link between cell division and ageing and therefore a knowledge of the cell division process can help understand both the natural process of ageing and the origin of early ageing-related diseases. Complex control and surveillance mechanisms have evolved to ensure the fidelity and robustness of cell division. The genetic material - DNA - is compacted into chromosomes during cell division and is not accessible for the production of new factors. Therefore, the mechanisms that control cell division rely in large part on the regulation of the function and activity of proteins that have been generated before cells begin dividing. One class of proteins that play a key role in controlling the accuracy and fidelity of cell division are the serine/threonine kinases. These kinases can regulate the function, dynamics and activity of numerous other cell division proteins, known as substrates, by adding phosphate groups - a process know as phosphorylation - that alter the mechanical and structural properties of their targets. The goal of this project is to dissect the role of one of this kinase, Citron kinase (CIT-K), which controls different aspects of cell division. We propose to use cutting edge post-genomic technologies to identify all the substrates of CIT-K throughout cell division and to understand how CIT-K is itself regulated through phosphorylation by other kinases. As CIT-K has been linked to human primary microcephaly and proposed as a potential target in anti-cancer therapy, our research will not only help understand key mechanisms that control cell division and proliferation, but will also lay the foundation for the development of future therapies for the treatment of these human pathologies.