Chromatin PTEN: Its Regulation And Functions

染色质 PTEN：其调控和功能

基本信息

批准号：
10200691
负责人：
WEI DAI
金额：
$ 38.35万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200691
关键词：
Affect Alleles Aneuploidy Antineoplastic Agents Biochemical C-terminal Cancer Etiology Cell Cycle Cell Cycle Arrest Cell Proliferation Cell division Cell physiology Chromatin Chromosomal Instability Chromosomal Stability Cleaved cell DNA Damage DNA Repair Development Drug Design Excision Genes Genome Stability Genomic Instability Genotoxic Stress Glioblastoma Human In Vitro Individual Inherited Lead Lipids MG132 Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Mitosis Mitotic Molecular Molecular Analysis Molecular Target Monoubiquitination Mus Mutate Mutation Normal Cell Nuclear Nuclear Import Nuclear Translocation PDPK1 gene PTEN gene Phosphatidylinositol 4,5-Diphosphate Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Polyubiquitination Post-Translational Protein Processing Predisposition Process Protein Kinase RNA Interference Regulation Reporting Research Role Second Messenger Systems Serine Signal Pathway Signal Transduction Tail Testing Threonine Tumor Suppressor Proteins Work angiogenesis cell growth drug development in vitro Model in vivo interest malignant breast neoplasm mouse model multicatalytic endopeptidase complex phosphatidylinositol 3,4,5-triphosphate phosphatidylinositol 3,4-diphosphate segregation tumor tumorigenesis ubiquitin-protein ligase

项目摘要

Chromatin PTEN: Its Regulation And Function Phosphatase and tensin homolog (PTEN) functions as a major negative regulator of the PI3K signaling pathway. PTEN is frequently mutated in a variety of human malignancies including glioblastoma, prostate cancer, and breast cancer. Inherited PTEN mutations cause cancer-susceptibility conditions. PTEN is also known to have nuclear/chromatin functions, deregulation of which apparently causes chromosomal instability. However, the exact functions of chromatin PTEN and its molecular regulation remain poorly understood. Past research shows that proper subcellular localization of PTEN after genotoxic stress is regulated by molecular mechanisms that involve post-translational modifications. We recently demonstrated that chromatin PTEN significantly increases during mitosis, coinciding with an increase in PTEN phosphorylation in the C-terminal tail. Biochemical and molecular analyses revealed that Plk1 was responsible for PTEN phosphorylation on S380, a residue not targeted by any other known kinases. We and others have shown that PTEN specifically interacts with Cdh1 (APC/CCdh1) and WWP2, two ubiquitin E3 ligases. Chromatin PTEN removal during mitotic exit and the physical interaction between PTEN and Cdh1 was a proteasome-dependnent process. Furthermore, we observed that a cleaved form of WWP2 specifically is enriched during G2 and mitotic stages, correlating with chromatin PTEN accumulation. WWP2 silencing accelerates mitotic progression. We hypothesize that chromatin PTEN plays a crucial role in mitotic progression, whose subcellular localization and function are controlled by Plk1, Cdh1 and WWP2, and that its molecular deregulation leads to chromosomal instability and tumor development. To test the validity of our hypothesis, we will determine whether and how phosphorylation facilitates chromatin translocation of PTEN, dissect the role of PTEN ubiquitin E3 ligases in regulating its stability, and study the phosphatase-independent function of PTEN in supressing chromosomal instability and tumor development using both in vivo and in vitro models. Our proposed studies will not only elucidate the molecular mechanism by which chromatin PTEN is regulated during the cell cycle, but will also reveal how PTEN functions in maintaining chromosomal stability and suppressing malignant transformation. This line of research can lead to the identification of new molecular targets in the PTEN regulatory network that can be explored for cancer drug designs and development.

染色质 PTEN：其调控和功能磷酸酶和张力蛋白同源物 (PTEN) 作为 PI3K 信号转导的主要负调节因子途径。 PTEN 在多种人类恶性肿瘤中经常发生突变，包括胶质母细胞瘤、前列腺癌癌症和乳腺癌。遗传性 PTEN 突变会导致癌症易感状况。 PTEN 也是已知具有核/染色质功能，其失调显然会导致染色体不稳定。然而，染色质 PTEN 的确切功能及其分子调控仍知之甚少。过去的研究表明，基因毒性应激后 PTEN 的正确亚细胞定位受到分子调控涉及翻译后修饰的机制。我们最近证明染色质 PTEN 有丝分裂期间显着增加，与 C 末端 PTEN 磷酸化的增加同时发生尾巴。生化和分子分析表明 Plk1 负责 PTEN 磷酸化 S380，任何其他已知激酶都不靶向的残基。我们和其他人已经证明 PTEN 特别与 Cdh1 (APC/CCdh1) 和 WWP2（两种泛素 E3 连接酶）相互作用。有丝分裂期间染色质 PTEN 去除 PTEN 和 Cdh1 之间的物理相互作用是蛋白酶体依赖性过程。此外，我们观察到 WWP2 的切割形式在 G2 和有丝分裂阶段特别富集，与染色质 PTEN 积累相关。 WWP2 沉默加速有丝分裂进程。我们假设染色质 PTEN 在有丝分裂进展中起着至关重要的作用，其亚细胞定位和功能由 Plk1、Cdh1 和 WWP2 控制，其分子失调导致染色体不稳定和肿瘤发展。为了检验我们假设的有效性，我们将确定磷酸化是否以及如何促进 PTEN 染色质易位，剖析其作用 PTEN泛素E3连接酶调节其稳定性，并研究PTEN的磷酸酶非依赖性功能使用体内和体外模型抑制染色体不稳定和肿瘤发展。我们的拟议的研究不仅将阐明染色质 PTEN 调节的分子机制细胞周期期间，还将揭示 PTEN 如何在维持染色体稳定性和抑制恶变。这一系列的研究可以导致新分子的鉴定 PTEN 监管网络中的目标可用于癌症药物设计和开发。