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

有丝分裂激酶Citron激酶在细胞分裂中的调控及功能分析

• 批准号: BB/R001227/1
• 负责人: Pier Paolo D'Avino
• 金额: $ 51.15万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR001227%2F1
• 关键词: Analysis; regulation; function; mitotic; kinase

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.

细胞是包括人类在内的许多生物体的基石。所有这些生物体的生长、发育和繁殖都依赖于细胞分裂的准确和迷人的过程，细胞分裂忠实地将遗传信息分配给两个分裂的细胞。适当的细胞分裂对于决定细胞命运和组织结构也至关重要。在这个过程中的错误是许多遗传疾病的原因，包括唐氏综合症，小头畸形，不育症和癌症。因此，彻底了解控制细胞分裂的机制可能会导致开发出针对这些遗传性疾病的新型治疗方法。此外，最近的证据也表明细胞分裂和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早期衰老相关疾病的起源。复杂的控制和监督机制已经发展，以确保细胞分裂的保真度和鲁棒性。遗传物质- DNA -在细胞分裂过程中被压缩成染色体，并且无法产生新的因子。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中起关键作用的一类蛋白质是丝氨酸/苏氨酸激酶。这些激酶可以调节许多其他细胞分裂蛋白质的功能，动力学和活性，称为底物，通过添加磷酸基团-一个称为磷酸化的过程-改变其目标的机械和结构特性。该项目的目标是剖析这种激酶之一，柠檬激酶（CIT-K）的作用，它控制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识别整个细胞分裂过程中CIT-K的所有底物，并了解CIT-K本身如何通过其他激酶的磷酸化来调节。由于CIT-K与人类原发性小头畸形症有关，并被提议作为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开发奠定基础。

项目成果

Purification of Recombinant ESCRT-III Proteins and Their Use in Atomic Force Microscopy and In Vitro Binding and Phosphorylation Assays.

重组 ESCRT-III 蛋白的纯化及其在原子力显微镜以及体外结合和磷酸化测定中的应用。

• DOI: 10.1007/978-1-4939-9492-2_15
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Capalbo L

Midbody Proteins Display Distinct Dynamics during Cytokinesis.

中体蛋白质在细胞分裂过程中表现出独特的动力学。

• DOI: 10.17863/cam.91642
• 发表时间: 2022
• 作者: Halcrow E

The midbody interactome reveals new unexpected roles for PP1 phosphatases in cytokinesis

中体相互作用组揭示了 PP1 磷酸酶在胞质分裂中新的意想不到的作用

• DOI: 10.1101/569459
• 发表时间: 2019
• 作者: Capalbo L