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ROCK II-mediated regulation of centrosome duplication / centrosome amplification

ROCK II 介导的中心体复制/中心体扩增调节

基本信息

批准号：
8510660
负责人：
KENJI FUKASAWA
金额：
$ 31.11万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510660
关键词：
Abbreviations Affinity Aneuploidy Aphidicolin Binding CDK2 gene Cancer Control Cancer Intervention Cell Cycle Cells Centrioles Centrosome Characteristics Chromosomal Instability Chromosomal Stability Chromosome Segregation Chromosomes Cyclin E Defect Development Dissection Event Fibroblasts Frequencies GTP Binding Generations Green Fluorescent Proteins Growth Factor Receptors Guanine Nucleotide Exchange Factors Guanosine Triphosphate Hepatocyte Growth Factor In Vitro Location Malignant - descriptor Malignant Neoplasms Mediating Mitosis Mitotic Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutate Mutation NPM1 gene Oncogene Proteins Oncogenic Pathway interactions Phosphorylation Phosphotransferases Play Proliferating Protein Tyrosine Kinase Proteins Proto-Oncogene Protein c-met Protocols documentation Receptor Protein-Tyrosine Kinases Regulation Research Project Grants Research Proposals Rho-associated kinase Role Signal Transduction Skin Solid Neoplasm Substrate Specificity Transducers Tumor Suppressor Proteins base cancer cell cell transformation chromosome loss daughter cell genetic regulatory protein leukemia/lymphoma malignant phenotype meetings mutant myosin light chain 2 nucleophosmin physical separation public health relevance receptor red fluorescent protein rho tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Chromosome instability (and resulting aneuploidy) has been recognized as a hallmark of cancer cells, and contributes to tumor progression by facilitating the genetic alterations required for acquisition of malignant phenotypes. Numerous studies have shown the frequent occurrence of abnormal amplification of centrosomes (generation of more than two centrosomes) in almost all types of solid tumors and certain types of lymphoma and leukemia, and the strong association between occurrence of centrosome amplification and aneuploidy. The detrimental consequence of centrosome amplification is prominently featured during mitosis: the presence of multiple centrosomes (spindle poles) results in mitotic defects, leading to an increased frequency of chromosome segregation errors. Indeed, centrosome amplification is now widely accepted as one of the major factors that contribute to chromosome instability in cancer. Centrosome amplification is caused primarily by uncontrolled duplication of centrosomes in a single cell cycle. We have recently found that ROCK II (Rho-associated kinase) localizes to centrosomes, and acts as a key regulatory protein for the initiation of centrosome duplication in association with nucleophosmin (NPM/B23). NPM/B23 is one of the major targets of CDK2-cyclin E, which plays a key role in initiating centrosome duplication. CDK2-cyclin E-mediated phosphorylation renders NPM/B23 a higher binding affinity to ROCK II, and ROCK II becomes super- activated by NPM/B23 binding. ROCK II then promotes the initiation of centrosome duplication in a centrosome localization- and kinase activity-dependent manner. ROCK II activation is also controlled by binding to an activated Rho protein (Rho-GTP), a major signal transducer downstream of many growth factor receptors (receptor tyrosine kinases/RTKs). These observations put forward to a model, in which two pathways (CDK2-NPM/B23 pathway and RTK-Rho-ROCK II pathway) converge by the physical interaction between ROCK II and NPM/B23 and super-activation of ROCK II to initiate centrosome duplication. In this research proposal, we will molecularly dissect the how ROCK II is controlled by these cancer-associated proteins to drive centrosome duplication, and how ROCK II controls centrosome duplication through focusing of the protein called LASP1, which we have recently identified as a potential centrosomal target of ROCK II for the initiation of centrosome duplication. Based on the facts that centrosome duplication occurs only in proliferating cells, and centrosome amplification is the major cause of chromosome instability in cancer, centrosome duplication and centrosome amplification can be effective targets for the cancer intervention protocols. Our research proposal that aim to understand the molecular mechanisms of the regulation of centrosome duplication and induction of centrosome amplification will provide vital information on this regard. PUBLIC HEALTH RELEVANCE: Cancer is the result of accumulation of many genetic alterations. Gain or loss of chromosomes (chromosome instability), which occurs frequently in cancer, introduces many genetic alterations simultaneously, hence accelerating tumors to acquire further malignant characteristics. In this research grant application, we will examine the mechanisms of how various oncoproteins and tumor suppressors, which are frequently mutated in cancer, maintain the integrity of chromosomes via controlling the duplication of centrosomes. The centrosome plays a critical role in the accurate segregation of chromosomes to two daughter cells during mitosis. Mutations of those oncoproteins and tumor suppressor proteins result in numeral abnormality of centrosomes, leading to mitotic defects and consequentially destabilization of chromosomes. As centrosome duplication occurs in actively proliferating cells such as cancer cells, centrosome duplication can be an effective target of cancer intervention, and the findings from our proposed studies will provide critical information on the development of superior cancer intervention protocols targeting centrosomes and cancer-associated proteins that control centrosome duplication.

描述（由申请方提供）：染色体不稳定性（以及由此产生的非整倍性）已被认为是癌细胞的标志，并通过促进获得恶性表型所需的遗传改变而促进肿瘤进展。大量研究表明，中心体异常扩增（产生两个以上的中心体）在几乎所有类型的实体瘤和某些类型的淋巴瘤和白血病中频繁发生，并且中心体扩增的发生与非整倍体之间存在强关联。中心体扩增的有害后果在有丝分裂期间具有显著特征：多个中心体（纺锤体极）的存在导致有丝分裂缺陷，导致染色体分离错误频率增加。事实上，中心体扩增现在被广泛认为是导致癌症中染色体不稳定的主要因素之一。中心体扩增主要由单个细胞周期中中心体的不受控制的复制引起。我们最近发现，ROCK II（Rho相关激酶）定位于中心体，并作为一个关键的调节蛋白与核磷蛋白（NPM/B23）启动中心体复制。NPM/B23是CDK 2-cyclin E的主要靶点之一，在启动中心体复制中起关键作用。CDK 2-细胞周期蛋白E介导的磷酸化使NPM/B23对ROCK II具有更高的结合亲和力，并且ROCK II通过NPM/B23结合而变得超活化。然后ROCK II以中心体定位和激酶活性依赖的方式促进中心体复制的起始。ROCK II激活也通过与活化的Rho蛋白（Rho-GTP）结合来控制，Rho蛋白是许多生长因子受体（受体酪氨酸激酶/RTK）下游的主要信号转导物。这些观察结果提出了一个模型，其中两条途径（CDK 2-NPM/B23途径和RTK-Rho-ROCK II途径）通过ROCK II和NPM/B23之间的物理相互作用和ROCK II的超激活而会聚以启动中心体复制。在这项研究计划中，我们将从分子水平上剖析ROCK II如何受这些癌症相关蛋白的控制来驱动中心体复制，以及ROCK II如何通过聚焦称为LASP 1的蛋白来控制中心体复制，我们最近发现LASP 1是ROCK II启动中心体复制的潜在中心体靶点。基于中心体复制仅发生在增殖细胞中，并且中心体扩增是癌症中染色体不稳定性的主要原因的事实，中心体复制和中心体扩增可以是癌症干预方案的有效靶点。我们的研究计划旨在了解中心体复制调控和诱导中心体扩增的分子机制，这将在这方面提供重要的信息。公共卫生相关性：癌症是许多遗传变异积累的结果。在癌症中经常发生的染色体获得或丢失（染色体不稳定性）同时引入许多遗传改变，从而加速肿瘤获得进一步的恶性特征。在这项研究资助申请中，我们将研究在癌症中经常突变的各种癌蛋白和肿瘤抑制因子如何通过控制中心体的复制来维持染色体的完整性。在有丝分裂过程中，中心体在染色体精确分离到两个子细胞中起着关键作用。这些癌蛋白和抑癌蛋白的突变导致中心体数目异常，导致有丝分裂缺陷和染色体不稳定。由于中心体复制发生在活跃增殖的细胞如癌细胞中，中心体复制可以是癌症干预的有效靶点，我们提出的研究结果将为开发针对中心体和控制中心体复制的癌症相关蛋白的上级癌症干预方案提供关键信息。