Chromatin PTEN: Its Regulation And Functions

染色质 PTEN：其调控和功能

• 批准号: 10411363
• 负责人: WEI DAI
• 金额: $ 8.7万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411363
• 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

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的调控及其功能 磷酸酶和张力蛋白同源蛋白(PTEN)是PI3K信号转导的主要负调控因子 路径。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。遗传的PTEN突变会导致癌症易感性疾病。PTEN也是 已知具有核/染色质功能，其放松调控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然知之甚少。过去时 研究表明，基因毒性应激后PTEN的适当亚细胞定位受分子调控 涉及翻译后修改的机制。我们最近证明了染色质PTEN 在有丝分裂过程中显著增加，与PTEN在C末端的磷酸化增加一致 尾巴。生化和分子分析表明，Plk1参与了PTEN的磷酸化。 S380，一个没有被任何其他已知的激酶靶向的残基。我们和其他人已经证明了PTEN特别是 与泛素E3连接酶CDH1(APC/CCdh1)和WWP2相互作用。有丝分裂过程中染色质PTEN的去除 PTEN与CDH1之间的物理相互作用是一个蛋白酶体依赖的过程。 此外，我们观察到WWP2的切割形式在G2期和有丝分裂期特异性地丰富， 与染色质PTEN积聚相关。WWP2沉默加速有丝分裂进程。我们 假设染色质PTEN在有丝分裂进程中起关键作用，其亚细胞 Plk1、CDH1和WWP2的定位和功能受Plk1、CDH1和WWP2的调控，其分子调控的解除 导致染色体不稳定和肿瘤的发展。为了测试我们假设的有效性，我们将 确定磷酸化是否以及如何促进PTEN的染色质转位，剖析PTEN的作用 PTEN泛素E3连接酶对其稳定性的调节，并研究PTEN的磷酸酶非依赖性功能 在体内和体外模型中抑制染色体不稳定性和肿瘤发展。我们的 拟议的研究不仅将阐明染色质PTEN被调控的分子机制 但也将揭示PTEN如何在维持染色体稳定和 抑制恶变。这条研究路线可能导致新分子的鉴定 PTEN调控网络中可用于抗癌药物设计和开发的靶点。