权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Cytokinesis

细胞分裂的机制

基本信息

批准号：
10675754
负责人：
Karen F Oegema
金额：
$ 46.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-02 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675754
关键词：
Actomyosin Address Anaphase Biological Assay C-terminal CDC2 gene Caenorhabditis elegans Cell Cycle Cell division Cell membrane Cells Centrosome Chromosome Segregation Chromosomes Competence Complement Complex Cyclin B Cytokinesis Cytoplasm DNA biosynthesis Data Diffusion Dimensions Embryo Failure Family GTPase-Activating Proteins Genetic Code Genomics Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human Investments Kinesin Life Malignant Neoplasms Measures Mediating Mediator Microtubule Bundle Microtubules Mitosis Mitotic Mitotic spindle Modeling Molecular Monitor Mothers Mutation N-terminal Nuclear Organism PLK1 gene Pattern Phase Phosphorylation Phosphotransferases Population Positioning Attribute Process Proteasome Inhibition Proteins Role Signal Transduction Specific qualifier value System TP53 gene Tertiary Protein Structure Testing Time Up-Regulation Work aurora kinase A chemotherapeutic agent constriction daughter cell dimer genome integrity inhibitor interest permissiveness preservation prevent rho screening

项目摘要

PROJECT SUMMARY After the chromosomes are segregated by the microtubule-based mitotic spindle, cytokinesis completes cell division, partitioning the contents of the mother cell to the two daughter cells. Cytokinesis is accomplished by constriction of an acto-myosin contractile ring that forms on the cortex in an equatorial band encircling the cell equator. Cytokinesis failure generates tetraploid cells that are a common intermediate in the genesis of cancers. Upregulation and mutation of cytokinesis regulators has also been implicated in different cancers, and inhibitors targeting cytokinesis are of interest as potential chemotherapeutic agents, motivating efforts to understand the mechanisms that pattern cortical contractility during cytokinesis. To ensure that each daughter cell receives an equivalent genomic complement, the position of the contractile ring is specified by the anaphase spindle. The spindle sends two superimposed signals to the cortex: (1) a positive signal promoting contractile ring assembly that is generated by set of bundled microtubules, called the central spindle, that forms between the separating chromosomes, and (2) a negative signal generated by the microtubule asters that suppresses the contractility of the non-equatorial cortex. The proposed work focuses on the molecular basis for these two signals that collectively direct contractile ring assembly. A central component of the positive signal promoting contractile ring assembly is centralspindlin, a tetrameric complex formed by a dimer of kinesin-6 and a dimer of CYK4. Centralspindlin is phosphorylated by the mitotic kinase PLK1, which concentrates on the central spindle; it subsequently diffuses to the adjacent plasma membrane where, through mechanisms that remain largely unclear, its CYK4 subunit engages with and activates the ECT2 guanine nucleotide exchange factor (GEF). Active ECT2 in turn generates an equatorial zone enriched for the master regulator of contractile ring assembly, RhoA-GTP. In Aim 1, we address the major open question with respect to positive cytokinesis signaling: the mechanism of ECT2 activation by centralspindlin. To understand how the microtubule asters suppress contractility on the non-equatorial cortex, which occurs at the same time as positive signaling from the central spindle, we developed an assay monitoring clearing of contractile ring proteins from the cell poles in the C. elegans embryo. Using this assay, we identified Aurora A kinase as an essential mediator of aster-based contractility suppression. In Aim 2, we build on this work to identify the Aurora A targets that mediate contractility suppression and extend analysis of this mechanism to human cells. Aim 3 addresses an important gap in understanding how the cell cycle state that supports contractile ring assembly is generated, and assesses whether the duration of cytokinesis, like that of mitosis, is monitored by a p53-based mitotic stopwatch mechanism that eliminates potentially problematic cells from the population.

项目总结