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Centrosome biogenesis and copy number control

中心体生物发生和拷贝数控制

基本信息

批准号：
10725065
负责人：
Brendan Cormack
金额：
$ 4.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10725065
关键词：
Animals Binding Biochemistry Biogenesis Biological Cell Cycle Regulation Cell Proliferation Cell division Cell physiology Cells Cellular Structures Centrioles Centrosome Chromosomes Cilia Competence Continuous Positive Airway Pressure Creativeness Cytoskeleton Defect Disease Ensure Functional disorder G1 Phase G2 Phase Gene Expression Genome Goals Growth Health Homeostasis Human Interphase Liquid substance Locomotion Malignant - descriptor Malignant Neoplasms Mediating Messenger RNA Microcephaly Microtubules Mitosis Mitotic spindle Molecular Movement Mus Noise Open Reading Frames Organelles PLK1 gene Phosphorylation Phosphorylation Site Play Procentriole Proteins Regulation Research Role Signal Transduction Structure Testing Translational Regulation Translations Variant Work daughter cell gene replacement genetic approach human disease imaging approach insight kinetosome protein degradation recruit scaffold tumorigenesis

项目摘要

Project Summary The long-term goal of our lab is to understand the molecular mechanisms that control centriole duplication and ensure the accurate distribution of the genome during cell division. Centrioles form the core of centrosomes, which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic spindle. Centrioles can also be modified to form basal bodies, which template the formation of cilia and play central roles in cellular signaling, fluid movement, and locomotion. To coordinate these diverse cellular processes, centriole copy number must be precisely controlled. Cells begin G1 phase with two centrioles, which are duplicated during S/G2 phase and are then carefully partitioned into both daughter cells during mitosis. We and others have shown that extra centrioles cause cell division errors that are sufficient to drive malignant transformation. Understanding the mechanism by which cells achieve the once per cycle duplication of the centrioles is, therefore, an important fundamental question of considerable relevance to human health. Although significant progress has been made in understanding the composition of centrioles, it remains unclear which specific steps in centriole formation are controlled by the enzymatic regulator Polo-like-kinase 4 (PLK4). Equally unclear is how a critical regulatory step, termed the ‘centriole-to-centrosome conversion’ (CCC), functions to maintain centriole homeostasis by enabling new centrioles to acquire competence for duplication. Our proposed research seeks to capitalize on our identification of key interactions and contributors to centriole formation to elucidate molecular mechanisms that control centriole assembly. We will examine three independent components of centriole biogenesis control: the translational regulation of PLK4 expression, the impact of PLK4 phosphorylation of specific substrates in centriole assembly, and the function of a new component required for the CCC. Aim 1 will define how a pair of conserved upstream open reading frames in the PLK4 mRNA regulate critical aspects of PLK4 expression. Aim 2 will mechanistically dissect how a critical PLK4 phosphorylation site we identified on STIL controls centriole assembly. Finally, Aim 3 will define how a new centriole protein, PPP1R35, functions to promote the CCC. Understanding how centriole assembly is regulated will reveal fundamental principles of organelle homeostasis and provide insight into the molecular basis of human diseases caused by centriole dysfunction.

项目总结

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A New Mode of Mitotic Surveillance.

DOI：
10.1016/j.tcb.2017.01.004
发表时间：
2017-05
期刊：
Trends in cell biology
影响因子：
19
作者：
Lambrus BG;Holland AJ
通讯作者：
Holland AJ

Binding of STIL to Plk4 activates kinase activity to promote centriole assembly.

DOI：
10.1083/jcb.201502088
发表时间：
2015-06-22
期刊：
The Journal of cell biology
影响因子：
0
作者：
Moyer TC;Clutario KM;Lambrus BG;Daggubati V;Holland AJ
通讯作者：
Holland AJ

Global Effects of DDX3 Inhibition on Cell Cycle Regulation Identified by a Combined Phosphoproteomics and Single Cell Tracking Approach.

DOI：
10.1016/j.tranon.2018.04.001
发表时间：
2018-06
期刊：
Translational oncology
影响因子：
5
作者：
Heerma van Voss MR;Kammers K;Vesuna F;Brilliant J;Bergman Y;Tantravedi S;Wu X;Cole RN;Holland A;van Diest PJ;Raman V
通讯作者：
Raman V

p53 protects against genome instability following centriole duplication failure.