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Regulation of cell cycle transition by a cyclin-dependent kinase in trypanosomes

锥虫中细胞周期蛋白依赖性激酶对细胞周期转变的调节

基本信息

批准号：
9896765
负责人：
Ziyin Li
金额：
$ 38.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-13 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896765
关键词：
African Trypanosomiasis Animals Binding Biochemical Biological Blood Circulation Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cell physiology Cells Complex Coupled Coupling Cyclin-Dependent Kinases Cyclins DNA Replication Factor DNA biosynthesis Disease Drug Targeting Eukaryota Exhibits G1/S Transition G2/M Transition Goals Human In Vitro Life Cycle Stages Mediating Methods Molecular Morphogenesis Mutate Outcome Study Parasites Parasitic Diseases Pathway interactions Peptide Initiation Factors Periodicity Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Pilot Projects Proteins Regulation Replication Initiation Role S Phase System Testing Translation Initiation Trypanosoma Trypanosoma brucei brucei Yeasts analog chemical genetics chemotherapy comparative drug development fungus genetic approach helicase in vivo insight knock-down novel vector vector-borne

项目摘要

Cyclin-dependent kinases (CDKs) are the fundamental regulators of the cell cycle in eukaryotes, which are activated by binding to cyclins whose abundance changes during the cell cycle. A single cyclin and multiple CDKs function in yeast cell cycle control, whereas multiple cyclins and multiple CDKs control the cell cycle progression in animals. Trypanosomes appear to employ a cell cycle control system that is strikingly different from that in fungi and animals. A PHO80-like cyclin, CYC2, and a CDK-related kinase, CRK1, control the G1/S transition, whereas a B-type cyclin, CYC6, and another CDK-related kinase, CRK3, govern the G2/M transition. However, how CRK1 exert their roles in cell cycle progression remains elusive, mainly because its downstream targets are not known. The current proposal aims to understand the mechanisms underlying the G1/S cell cycle transition and the molecular basis for the distinct cell cycle regulation between different life cycle forms of T. brucei. In aim 1 of this proposal, we plan to apply chemical genetic approach to identify CRK1 substrates from the procyclic and bloodstream forms and to comparatively analyze the CRK1-regulated cellular pathways between the two forms. Aim 2 is to understand the mechanisms underlying the cell cycle-dependent protein translation initiation, with a focus on the regulation of two translation initiation factors by CRK1. Aim 3 is to dissect the role of CRK1 in DNA replication initiation by investigating CRK1-mediated regulation of the DNA replication factors in the Cdc45-Mcm2-7-GINS complex. Through molecular, cell biological, chemical genetic, and biochemical approaches, our overall goal in this proposal is to understand the mechanistic roles of CRK1 in the G1/S control through regulating the DNA replicative helicase and in G1-specific protein translation initiation through regulating translation initiation factors. The outcomes from these studies not only will significantly advance our understanding of the mechanisms of cell cycle transitions in trypanosomes, but also could validate CRK1 and its trypanosome-specific downstream pathways as drug targets for anti-trypanosome chemotherapy.

细胞周期蛋白依赖性激酶（CDKs）是真核生物细胞周期的基本调节因子，通过与细胞周期蛋白结合而被激活，细胞周期蛋白的丰度在细胞周期中发生变化。单个细胞周期蛋白和多个 CDK在酵母细胞周期控制中起作用，而多种细胞周期蛋白和多种CDK控制细胞周期动物的进步锥虫似乎采用一种细胞周期控制系统，从真菌和动物中分离出来。一种PHO 80样细胞周期蛋白CYC 2和一种CDK相关激酶CRK 1控制着G1/S G2/M转换由B型细胞周期蛋白CYC 6和另一种CDK相关激酶CRK 3控制。然而，CRK 1如何发挥其在细胞周期进程中的作用仍然是难以捉摸的，主要是因为其下游目标不明。目前的建议旨在了解G1/S细胞的机制细胞周期转换和不同生命周期形式之间的不同细胞周期调节的分子基础， T.布鲁塞。在本计划的目标1中，我们计划应用化学遗传学方法来鉴定CRK 1底物从前循环和血流形式，并比较分析CRK 1调节的细胞通路两种形式之间。目的二是了解细胞周期依赖蛋白的作用机制翻译起始，重点是CRK 1对两个翻译起始因子的调控。目标3是通过研究CRK 1介导的DNA复制调控，剖析CRK 1在DNA复制起始中的作用 Cdc 45-Mcm 2 -7-GINS复合物中的复制因子。通过分子、细胞生物学、化学遗传学，和生物化学方法，我们在这个建议中的总体目标是了解CRK 1的机制作用通过调节DNA复制解旋酶参与G1/S调控，并参与G1特异性蛋白质翻译通过调控翻译起始因子来启动。这些研究的结果不仅将显著推进我们对锥虫细胞周期转换机制的理解，但也可以验证CRK 1及其锥虫特异性下游途径作为抗锥虫的药物靶点化疗