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）：细胞增殖和存活的控制是维持健康细胞群和消除那些在适当的细胞周期控制方面有缺陷的细胞的关键因素。调节细胞周期和细胞凋亡的关键蛋白是 p53，这是一种在超过 50% 的人类癌症中发生突变的蛋白。我们最近发现 p53 和 stathmin（一种微管不稳定蛋白）的联合丢失会导致细胞周期延迟在细胞周期的 G2 期并导致细胞凋亡。这些数据提供了对控制细胞增殖的控制的深入了解，并有可能确定特异性杀死那些缺乏功能性 p53 的肿瘤细胞的靶标。本申请中提出的实验旨在确定与 Stathmin 水平降低和细胞周期 G2 期进展延迟相关的信号通路。完成所提出的目标将检验这样的假设：stathmin 耗尽可以稳定间期微管细胞骨架，其在下游发挥作用，限制 Aurora A 的 Rho 依赖性激活和有丝分裂进入。在整个目标中，还测试了替代模型。在目标 1 中，将识别 stathmin 耗尽下游的信号中继。药物诱导的微管解聚或稳定将用于测试其消除（解聚）或模拟（稳定）观察到的 G2 延迟的能力。其他 stathmin 结合伴侣 p27Kip1 和 STAT3 将在 stathmin 耗尽后测试其在调节细胞周期进程中的潜在作用。 Stathmin 截短的过度表达将用于进一步探测间期细胞周期进展的微管依赖性或独立调节。在目标 2 中，将检查控制有丝分裂进入的途径在 Stathmin 耗尽后传递信号的作用。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以消除或模拟 Stathmin 耗尽引起的 G2 延迟。完成这两个目标将确定连接 Stathmin 消耗和有丝分裂进入的信号级联。公共卫生相关性：控制癌细胞增殖需要采取干预措施来阻止细胞复制，理想情况下不影响体内未转化的细胞。我们已经鉴定出微管不稳定蛋白 Stathmin 是缺乏肿瘤抑制因子 p53 的癌细胞繁殖和生存所必需的蛋白质。由于大约一半的人类癌症都存在 p53 突变，了解为什么这些细胞中的细胞增殖需要 stathmin 具有选择性控制其生长的巨大潜力。