Dissecting the role of TPX2 during cell division
剖析 TPX2 在细胞分裂过程中的作用
基本信息
- 批准号:RGPIN-2014-04970
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2014
- 资助国家:加拿大
- 起止时间:2014-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Dissecting the role of TPX2 during cell division Maintaining a stable genome is essential for the growth and development of multicellular organisms. The two key steps in maintaining a stable genome are accurate error free duplication and equal segregation of the genome in the two newly forming cells during cell division. A failure to correctly segregate the genome leads to aneuploidy, a condition that either leads to cell death or mis-regulated cells. The cell therefore tightly regulates cell division to ensure its success; however, at present we still have a poor understanding of the molecular mechanisms that drive and regulate this fundamental process. Completion of cell division in all eukaryotic cells requires the sequential re-organization of the microtubule network. Each organization state performs specific functions: aligning chromosomes during metaphase, separating sister chromosomes during anaphase, stimulating furrow ingression during early cytokinesis and assembling the midbody for the completion of cytokinesis. Therefore, it is vital to determine the molecular events that orchestrate the transitions between these microtubule organization states in order to understand how one cell divides into two. As there is little protein synthesis during mitosis, the transitions between these microtubule organization states are likely due to post-translational modifications that alter the activity of the mitotic proteome between the different mitotic phases. A major contributor to changes in the mitotic proteome will be changes in protein phosphorylation. TPX2 is an essential microtubule binding protein that is phosphorylated and involved in the mitotic organization of microtubules. Our goal is to define the pathways that regulate TPX2 during mitosis. By building upon recent data and techniques developed in the lab, previously unappreciated functions and modes of TPX2 regulation will be identified. SPECIFIC AIMS Determine the role of TPX2 phosphorylation in cell division: We have identified conserved Aurora A, Cdk1 and MAP kinase dependent phosphorylation sites on TPX2. Failure to phosphorylate TPX2 at the Aurora A sites results in the mislocalization of TPX2 within the cell, suggesting that Aurora A dependent phosphorylation is required for localization TPX2. Next we will determine which TPX2 functions are regulated by Aurora A dependent phosphorylation. We will focus on the early stages of mitosis when TPX2 and Aurora A localize to similar microtubule structures. Using RNAi rescue approaches in cells stably expressing inducible wildtype and mutant TPX2 (phosphomimetic and non-phosphorylatable mutants), we will assay the role of Aurora A dependent TPX2 phosphorylation in spindle assembly, spindle pole organization and kinetochore mediated microtubule nucleation. We will employ the same strategies to study the role of Cdk1 and MAP kinase dependent phosphorylation of TPX2. These approaches will determine how TPX2 is regulated during cell division. Determine the role of TPX2 in the late stages of cell division: We have observed TPX2 on the microtubules of the midbody during cytokinesis, suggesting unappreciated roles for TPX2 in cytokinesis. Using novel technology to specifically deplete TPX2 after metaphase, we will use assays already developed in the lab to dissect events at different stages of cytokinesis. Using these approaches we anticipate identifying novel roles for TPX2 in cytokinesis. SUMMARY: Combined these studies will determine how TPX2 regulates cell division by identifying new regulatory mechanisms and new functions for TPX2 in cytokinesis. As TPX2 occurs in plants and animals and has been implicated in apoptosis, these findings will further our understanding of cell division in all eukaryotic cells.
剖析 TPX2 在细胞分裂过程中的作用 维持稳定的基因组对于多细胞生物的生长和发育至关重要。维持稳定基因组的两个关键步骤是在细胞分裂过程中两个新形成的细胞中基因组的准确无差错复制和平等分离。未能正确分离基因组会导致非整倍性,这种情况要么导致细胞死亡,要么导致细胞失调。因此,细胞严格调控细胞分裂以确保其成功;然而,目前我们对驱动和调节这一基本过程的分子机制仍然知之甚少。所有真核细胞的细胞分裂的完成都需要微管网络的顺序重组。每个组织状态执行特定的功能:在中期排列染色体,在后期分离姐妹染色体,在早期胞质分裂期间刺激沟进入以及组装中间体以完成胞质分裂。因此,为了了解一个细胞如何分裂成两个,确定协调这些微管组织状态之间转变的分子事件至关重要。由于有丝分裂期间几乎没有蛋白质合成,这些微管组织状态之间的转变可能是由于翻译后修饰改变了不同有丝分裂阶段之间有丝分裂蛋白质组的活性。有丝分裂蛋白质组变化的一个主要贡献者是蛋白质磷酸化的变化。 TPX2 是一种必需的微管结合蛋白,它被磷酸化并参与微管的有丝分裂组织。我们的目标是确定有丝分裂期间调节 TPX2 的途径。通过利用实验室开发的最新数据和技术,将确定以前未被重视的 TPX2 调节功能和模式。具体目标 确定 TPX2 磷酸化在细胞分裂中的作用:我们已经鉴定了 TPX2 上保守的 Aurora A、Cdk1 和 MAP 激酶依赖性磷酸化位点。 Aurora A 位点磷酸化 TPX2 失败会导致 TPX2 在细胞内错误定位,这表明 Aurora A 依赖性磷酸化是 TPX2 定位所必需的。接下来我们将确定哪些 TPX2 功能受到 Aurora A 依赖性磷酸化的调节。我们将重点关注有丝分裂的早期阶段,此时 TPX2 和 Aurora A 定位于相似的微管结构。在稳定表达诱导型野生型和突变型 TPX2(拟磷酸化和不可磷酸化突变体)的细胞中使用 RNAi 拯救方法,我们将测定 Aurora A 依赖性 TPX2 磷酸化在纺锤体组装、纺锤体极组织和动粒介导的微管成核中的作用。我们将采用相同的策略来研究 Cdk1 和 MAP 激酶依赖性 TPX2 磷酸化的作用。这些方法将决定 TPX2 在细胞分裂过程中如何受到调节。确定 TPX2 在细胞分裂后期的作用:我们在胞质分裂过程中观察到 TPX2 在中体微管上,这表明 TPX2 在胞质分裂中的作用未被充分认识。使用新技术在中期后特异性地消耗 TPX2,我们将使用实验室中已开发的检测方法来剖析胞质分裂不同阶段的事件。使用这些方法,我们预计确定 TPX2 在胞质分裂中的新作用。摘要:结合这些研究将通过确定 TPX2 在胞质分裂中的新调节机制和新功能来确定 TPX2 如何调节细胞分裂。由于 TPX2 存在于植物和动物中并与细胞凋亡有关,这些发现将进一步加深我们对所有真核细胞细胞分裂的理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Wilde, Andrew其他文献
Cleavage Furrow Organization Requires PIP2-Mediated Recruitment of Anillin
- DOI:
10.1016/j.cub.2011.11.040 - 发表时间:
2012-01-10 - 期刊:
- 影响因子:9.2
- 作者:
Liu, Jinghe;Fairn, Gregory D.;Wilde, Andrew - 通讯作者:
Wilde, Andrew
Dynamic release of nuclear RanGTP triggers TPX2-dependent microtubule assembly during the apoptotic execution phase
- DOI:
10.1242/jcs.037259 - 发表时间:
2009-03-01 - 期刊:
- 影响因子:4
- 作者:
Moss, David K.;Wilde, Andrew;Lane, Jon D. - 通讯作者:
Lane, Jon D.
CDK11p58?cyclin L1? regulates abscission site assembly
- DOI:
10.1074/jbc.ra119.009107 - 发表时间:
2019-12-06 - 期刊:
- 影响因子:4.8
- 作者:
Renshaw, Matthew J.;Panagiotou, Thomas C.;Wilde, Andrew - 通讯作者:
Wilde, Andrew
Importin β2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal
- DOI:
10.1074/jbc.m115.649160 - 发表时间:
2015-05-22 - 期刊:
- 影响因子:4.8
- 作者:
Chen, Anan;Akhshi, Tara K.;Wilde, Andrew - 通讯作者:
Wilde, Andrew
The scaffold-protein IQGAP1 enhances and spatially restricts the actin-nucleating activity of Diaphanous-related formin 1 (DIAPH1)
- DOI:
10.1074/jbc.ra119.010476 - 发表时间:
2020-03-06 - 期刊:
- 影响因子:4.8
- 作者:
Chen, Anan;Arora, Pam D.;Wilde, Andrew - 通讯作者:
Wilde, Andrew
Wilde, Andrew的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Wilde, Andrew', 18)}}的其他基金
Molecular regulation of abscission
脱落的分子调控
- 批准号:
RGPIN-2019-05782 - 财政年份:2022
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Molecular regulation of abscission
脱落的分子调控
- 批准号:
RGPIN-2019-05782 - 财政年份:2021
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Molecular regulation of abscission
脱落的分子调控
- 批准号:
RGPIN-2019-05782 - 财政年份:2020
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Molecular regulation of abscission
脱落的分子调控
- 批准号:
RGPIN-2019-05782 - 财政年份:2019
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Dissecting the role of TPX2 during cell division
剖析 TPX2 在细胞分裂过程中的作用
- 批准号:
RGPIN-2014-04970 - 财政年份:2018
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Dissecting the role of TPX2 during cell division
剖析 TPX2 在细胞分裂过程中的作用
- 批准号:
RGPIN-2014-04970 - 财政年份:2017
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Dissecting the role of TPX2 during cell division
剖析 TPX2 在细胞分裂过程中的作用
- 批准号:
RGPIN-2014-04970 - 财政年份:2016
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Dissecting the role of TPX2 during cell division
剖析 TPX2 在细胞分裂过程中的作用
- 批准号:
RGPIN-2014-04970 - 财政年份:2015
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
The role of RanGTP in the spatial organization of mitotic cells
RanGTP 在有丝分裂细胞空间组织中的作用
- 批准号:
356045-2008 - 财政年份:2012
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
The role of RanGTP in the spatial organization of mitotic cells
RanGTP 在有丝分裂细胞空间组织中的作用
- 批准号:
356045-2008 - 财政年份:2011
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
相似国自然基金
PfAP2-R介导的PfCRT转录调控在恶性疟原虫对喹啉类药物抗性中的作用及机制研究
- 批准号:82372275
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
Sestrin2抑制内质网应激对早产儿视网膜病变的调控作用及其机制研究
- 批准号:82371070
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
相似海外基金
The role of youth voluntary actions in Disaster Risk Reduction in the Ganges Brahmaputra and Meghna (GBM) delta
青年志愿行动在雅鲁藏布江和梅格纳河三角洲减少灾害风险中的作用
- 批准号:
2593674 - 财政年份:2025
- 资助金额:
$ 3.42万 - 项目类别:
Studentship
Size matters, but at what cost? Role of male sex hormones in the placenta
规模很重要,但代价是什么?
- 批准号:
DP240102256 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Projects
What is the role of striatal dopamine in value-based decision-making?
纹状体多巴胺在基于价值的决策中发挥什么作用?
- 批准号:
DP240103246 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Projects
Understanding the role of trauma in alcohol and other drug-related problems
了解创伤在酒精和其他毒品相关问题中的作用
- 批准号:
DP240101473 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Projects
The Role of Climate Change in Early Human Behavioural Evolution
气候变化在早期人类行为进化中的作用
- 批准号:
2903287 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Studentship
FORTIFY - From Molecular Physiology to Biophysics of the Glymphatic System: a Regulatory Role for Aquaporin-4
FORTIFY - 从类淋巴系统的分子生理学到生物物理学:Aquaporin-4 的调节作用
- 批准号:
EP/Y023684/1 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Research Grant
Mechanisms of Motivation: The Role of Cortical-Basal Ganglia-Dopamine Circuits in Reward Pursuit and Apathy
动机机制:皮质-基底神经节-多巴胺回路在奖励追求和冷漠中的作用
- 批准号:
MR/X022080/1 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Research Grant
A human slice model to understand the role of fibrosis in children with bladder exstrophy
人体切片模型了解纤维化在膀胱外翻儿童中的作用
- 批准号:
MR/X030946/1 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Research Grant
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Fellowship
Investigating the role of complement component 5a in ANCA-associated vasculitis
研究补体成分 5a 在 ANCA 相关血管炎中的作用
- 批准号:
MR/Y000854/1 - 财政年份:2024
- 资助金额:
$ 3.42万 - 项目类别:
Fellowship