Signal Transduction by the Microtubule Destabilizer, Stathmin/Oncoprotein 18

微管去稳定剂 Stathmin/癌蛋白 18 的信号转导

基本信息

批准号：
8231184
负责人：
LYNNE CASSIMERIS
金额：
$ 36.53万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2015-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231184
关键词：
Address Apoptosis Binding Bypass Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Death Cell Proliferation Cell Survival Cell division Cells Clinic Commit Cyclin B Cyclins Cytoskeleton Data Development Drug Delivery Systems Enzymes G2 Phase Goals Growth Human Interphase Interphase Cell Intervention Link Malignant Neoplasms Measures Mentors Microtubule Depolymerization Microtubule Stabilization Microtubules Mitosis Mitotic Modeling Mutate Mutation Normal Cell Paclitaxel Pathway interactions Pharmaceutical Preparations Phase Population Process Protein p53 Proteins Publications Regulation Regulatory Pathway Reproduction Role STAT3 gene Signal Pathway Signal Transduction Students Testing Time Toxic effect Work alternative treatment cancer cell chemotherapy cyclin A2 depolymerization design graduate student human STK6 protein insight killings neoplastic cell protein function research study rho rho GTP-Binding Proteins stathmin success

项目摘要

DESCRIPTION (provided by applicant): The control of cell proliferation and survival are critical factors in maintaining healthy cell populations and eliminating those cells defective in proper cell cycle control. A key protein regulating the cell cycle and apoptosis is p53, a protein mutated in >50% of human cancers. We recently found that the combined loss of both p53 and stathmin, a microtubule destabilizing protein, results in a cell cycle delay during the G2 phase of the cell cycle and cell death by apoptosis. These data provide insight into controls governing cell proliferation and hold the potential to identify targets to kill specifically those tumor cells lacking functional p53. Experiments proposed in this application look to identify the signal pathway linking reduced stathmin level and delayed progression through the G2 phase of the cell cycle. Completion of the proposed aims will test the hypothesis that stathmin depletion stabilizes the interphase microtubule cytoskeleton, which acts downstream to limit Rho-dependent activation of Aurora A and mitotic entry. Throughout the aims, alternative models are also tested. In Aim 1, the signal relay downstream of stathmin depletion will be identified. Drug-induced microtubule depolymerization or stabilization will be used to test for their ability to abrogate (depolymerization) or mimic (stabilization) the observed delay in G2. The other stathmin binding partners, p27Kip1 and STAT3, will be tested for their potential role(s) in regulating cell cycle progression after stathmin depletion. Over-expression of stathmin truncations will be used to further probe for microtubule- dependent or -independent regulation of interphase cell cycle progression. In Aim 2, pathways controlling mitotic entry will be examined for their role in relaying signals after stathmin depletion. The levels of cyclins and their rate of accumulation will be measured, the activity states of enzymes directly controlling mitotic entry will be examined, and finally, upstream signal cascades will be manipulated to either abrogate or mimic the stathmin depletion-induced delay in G2. Completion of the two aims will identify the signal cascade linking stathmin depletion and mitotic entry. PUBLIC HEALTH RELEVANCE: Controlling cancer cell proliferation requires interventions that can block cell replication, ideally without impacting the non-transformed cells in the body. We have identified the microtubule destabilizing protein, stathmin, as a protein necessary for reproduction and survival of cancer cells lacking the tumor suppressor p53. Since about half of all human cancers harbor mutations in p53, understanding why stathmin is required for cell proliferation in these cells holds great potential for selectively controlling their growth.

描述（由申请人提供）：控制细胞增殖和存活是维持健康细胞群体并消除这些细胞在适当细胞周期控制中有缺陷的关键因素。调节细胞周期和凋亡的关键蛋白质是p53，一种蛋白质在> 50％的人类癌症中突变。我们最近发现，p53和Stathmin（一种微管破坏蛋白质）的综合损失导致细胞周期循环的G2阶段和细胞凋亡的细胞死亡导致细胞周期延迟。这些数据提供了对控制细胞增殖的控制的洞察力，并具有识别靶标的潜力，以杀死缺乏功能性p53的那些肿瘤细胞。在此应用中提出的实验旨在识别连接降低的体育素水平和通过细胞周期G2阶段延迟进展的信号途径。所提出的目标的完成将检验以下假设，即稳定的耗竭稳定相互作用的微管细胞骨架，该骨骼的作用是限制Aurora A和有丝分裂输入的Rho依赖性激活的下游。在整个目标中，还测试了替代模型。在AIM 1中，将鉴定出Stathmin耗竭的下游信号继电器。药物诱导的微管解聚或稳定化将用于测试其废除（去聚合）或模拟（稳定）G2中观察到的延迟的能力。其他毒素结合伴侣P27KIP1和STAT3将测试其在调节斯塔明蛋白耗竭后调节细胞周期进程中的潜在作用。斯塔明截断的过表达将用于进一步探测微管依赖性或非依赖性的相互作用细胞周期进程的调节。在AIM 2中，将检查控制有丝分裂输入的途径，以便在耗尽处耗尽后传递信号中的作用。将测量细胞周期蛋白的水平及其积累速率，将检查直接控制有丝分裂进入的酶的活性状态，最后，将操纵上游信号级联反应以消除或模仿Stathmin Deptetion诱导的G2中的延迟。这两个目标的完成将确定连接Stathmin耗竭和有丝分裂输入的信号级联。公共卫生相关性：控制癌细胞增殖需要干预措施，可以阻止细胞复制，理想情况下，不会影响体内未转化的细胞。我们已经确定微管破坏了蛋白质，Stathmin是一种缺乏肿瘤抑制剂p53的癌细胞繁殖和存活所必需的蛋白质。由于大约一半的人类癌症中有p53中的突变，因此了解这些细胞中细胞增殖所必需的斯塔敏为何具有选择性控制其生长的巨大潜力。