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PTEN Deficiency and Tumor Development

PTEN 缺乏和肿瘤发展

基本信息

批准号：
8305969
负责人：
YUXIN YIN
金额：
$ 34.02万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305969
关键词：
1-Phosphatidylinositol 3-Kinase Affect Age Aneuploidy Applications Grants Biological Assay Bub1 protein C-terminal Cell division Cells Chromatin Chromosomal Instability Chromosomal Stability Chromosome Segregation Chromosome abnormality Chromosomes Cytoplasm Data Defect Development Dominant-Negative Mutation E2F1 gene Embryo Ensure Exhibits Fibroblasts Frequencies Functional disorder Genes Genome Genome Stability Genomic Instability Goals Human Impairment In Vitro Kinetochores Knock-in Mouse Knockout Mice Lead Light Location Lymphocyte Maintenance Malignant Neoplasms Mediating Mitosis Mitotic Mitotic Checkpoint Mitotic spindle Mitotic/Spindle Checkpoint Modeling Multiple Hamartoma Syndrome Mutate Mutation N-terminal Nuclear Null Lymphocytes PTEN gene Pathway interactions Patients Phosphoric Monoester Hydrolases Play Principal Investigator Process Proteins Proto-Oncogene Proteins c-akt Regulation Research Role Testing Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins Yin base chromatin immunoprecipitation gain of function in vivo insight interest mouse model mutant novel prevent programs promoter public health relevance response segregation therapeutic development tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): PTEN Deficiency and Tumor Development PTEN is one of the most frequently mutated genes in human cancer. We have previously demonstrated that PTEN plays an essential role in the maintenance of genomic stability and that PTEN controls genome integrity through multiple mechanisms. The mitotic checkpoint is the most important mechanism for ensuring accurate chromosome segregation during cell division. Our preliminary data show that knockdown of PTEN causes severe mitotic misalignment and increases the frequency of monopolar and multipolar spindles, suggesting that PTEN deficiency impairs kinetochore congression and spindle bipolarity. Moreover, disruption of Pten eliminates the mitotic checkpoint response to spindle damage. Of significant interest was our finding that the levels of Bub1 and aurora B which are two critical mitotic checkpoint regulators are reduced in Pten null cells. In this grant application, we propose that PTEN plays a critical role in mitotic checkpoint control and spindle assembly. Our first specific aim is to characterize how PTEN deficiency affects kinetochore functions, spindle assembly and mitotic checkpoint activity. To do so, we will identify potential kinetochore or spindle factors physically associated with PTEN during mitosis. We will also determine whether wild-type PTEN can correct mitotic errors and restore the mitotic checkpoint. Our second specific aim is to determine whether the phosphatase activity of PTEN is necessary for its mitotic function and further define the functional domain of PTEN responsible for bipolar spindle assembly and the mitotic checkpoint. A variety of PTEN mutants with and without the N-terminal phosphatase domain will be tested for their ability to establish spindle bipolarity, sustain the expression levels of checkpoint proteins, and maintain a functional mitotic checkpoint. Our third specific aim is to explore the mechanism of how PTEN participates in the regulation of Bub1 and aurora B in synergy with E2F-1. Our preliminary chromatin immunoprecipitation assays identified both PTEN and E2F-1 on the mitotic gene promoter, which suggests there is functional cooperation of PTEN and E2F-1 on chromatin. We will therefore determine how PTEN acts on chromatin to modulate the transcriptional regulation of mitotic genes by E2F-1. Our final specific aim will be to further evaluate the role of PTEN in controlling the mitotic checkpoint and chromosomal stability using a Cowden syndrome model where PTEN is inherently mutated. We will examine the mitotic checkpoint activity in human lymphocytes with mutant PTEN. We will characterize the gain of function of PTEN mutants and determine whether these dominant-negative PTEN mutants disrupt the mitotic checkpoint and induce chromosome instability. Finally, we will use a PTEN189 mutant knock-in mouse model to determine whether the PTEN189 mutation causes genomic instability and results in tumorigenesis. Successful completion of this project will define PTEN as a controller of the spindle checkpoint and a guardian of the genome. New findings from this project may provide insights into the mechanism whereby PTEN deficiency and consequent mitotic dysfunction lead to tumorigenesis. PUBLIC HEALTH RELEVANCE: PTEN Deficiency and Tumor Development Narrative The PTEN tumor suppressor is frequently mutated in a variety of human cancers. Loss of PTEN leads to tumorigenesis in mouse models. The mitotic checkpoint is a major mechanism for ensuring chromosome inheritance and preventing malignancy. This project will explore novel functions of nuclear PTEN in maintaining genomic stability by revealing its critical role in spindle assembly and chromosome segregation. New findings from this study will answer the fundamental question of how PTEN deficiency impairs the mitotic surveillance machinery, leading to tumor development. Identification of the PTEN-mitotic pathway may offer a profound implication for development of therapeutic strategies against tumorigenesis.

描述（由申请人提供）：PTEN缺陷和肿瘤发展PTEN是人类癌症中最常见的突变基因之一。我们以前已经证明，PTEN在维持基因组稳定性中起着至关重要的作用，并且PTEN通过多种机制控制基因组的完整性。有丝分裂检查点是确保细胞分裂过程中染色体精确分离的最重要机制。我们的初步数据表明，敲除PTEN导致严重的有丝分裂错位，并增加单极和多极纺锤体的频率，这表明，PTEN缺陷损害动粒大会和纺锤体双极性。此外，Pten的破坏消除了对纺锤体损伤的有丝分裂检查点反应。我们的研究发现Bub 1和Aurora B的水平在Pten无效细胞中降低，这两个关键的有丝分裂检查点调节因子具有重要意义。在这项拨款申请中，我们提出PTEN在有丝分裂检查点控制和纺锤体组装中发挥关键作用。我们的第一个具体目标是描述PTEN缺陷如何影响动粒功能、纺锤体组装和有丝分裂检查点活性。为了做到这一点，我们将确定潜在的动粒或纺锤体因子物理上与有丝分裂过程中的PTEN。我们还将确定野生型PTEN是否可以纠正有丝分裂错误并恢复有丝分裂检查点。我们的第二个具体目标是确定是否磷酸酶活性的PTEN是必要的，其有丝分裂功能，并进一步确定的功能域的PTEN负责双极纺锤体组装和有丝分裂检查点。将测试具有和不具有N-末端磷酸酶结构域的各种PTEN突变体建立纺锤体双极性、维持检查点蛋白的表达水平和维持功能性有丝分裂检查点的能力。我们的第三个具体目标是探索PTEN如何协同E2 F-1参与Bub 1和Aurora B的调节的机制。我们初步的染色质免疫沉淀分析鉴定了有丝分裂基因启动子上的PTEN和E2 F-1，这表明在染色质上存在PTEN和E2 F-1的功能合作。因此，我们将确定PTEN如何作用于染色质，以调节E2 F-1对有丝分裂基因的转录调控。我们最终的具体目标将是使用Cowden综合征模型进一步评估PTEN在控制有丝分裂检查点和染色体稳定性中的作用，其中PTEN是固有突变的。我们将研究突变的PTEN在人淋巴细胞中的有丝分裂检查点活性。我们将描述PTEN突变体功能的获得，并确定这些显性阴性的PTEN突变体是否破坏有丝分裂检查点并诱导染色体不稳定性。最后，我们将使用PTEN 189突变敲入小鼠模型来确定PTEN 189突变是否引起基因组不稳定性并导致肿瘤发生。该项目的成功完成将使PTEN成为纺锤体检查点的控制者和基因组的守护者。该项目的新发现可能为PTEN缺陷和随后的有丝分裂功能障碍导致肿瘤发生的机制提供见解。公共卫生关系：PTEN肿瘤抑制基因在多种人类癌症中频繁突变。在小鼠模型中，PTEN的缺失导致肿瘤发生。有丝分裂检查点是确保染色体遗传和防止恶性肿瘤的主要机制。本项目将通过揭示其在纺锤体组装和染色体分离中的关键作用来探索核PTEN在维持基因组稳定性方面的新功能。这项研究的新发现将回答PTEN缺陷如何损害有丝分裂监视机制，导致肿瘤发展的基本问题。PTEN-有丝分裂通路的鉴定可能为开发抗肿瘤发生的治疗策略提供深远的意义。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

DOI：
10.1016/j.cmet.2014.03.023
发表时间：
2014-05-06
期刊：
Cell metabolism
影响因子：
29
作者：
Liang H;He S;Yang J;Jia X;Wang P;Chen X;Zhang Z;Zou X;McNutt MA;Shen WH;Yin Y
通讯作者：
Yin Y

PTEN stabilizes TOP2A and regulates the DNA decatenation.

DOI：
10.1038/srep17873
发表时间：
2015-12-10
期刊：
Scientific reports
影响因子：
4.6
作者：
Kang X;Song C;Du X;Zhang C;Liu Y;Liang L;He J;Lamb K;Shen WH;Yin Y
通讯作者：
Yin Y

PTEN interacts with histone H1 and controls chromatin condensation.

DOI：
10.1016/j.celrep.2014.08.008
发表时间：
2014-09-25
期刊：
Cell reports
影响因子：
8.8
作者：
Chen ZH;Zhu M;Yang J;Liang H;He J;He S;Wang P;Kang X;McNutt MA;Yin Y;Shen WH
通讯作者：
Shen WH

PTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis.