Chromatin PTEN: Its Regulation And Functions
Chromatin PTEN: Its Regulation And Functions
批准号:
10411363
负责人:
WEI DAI
金额:
$8.7万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-01 至 2023-07-31
关键词:
AffectAllelesAneuploidyAntineoplastic AgentsBiochemicalC-terminalCancer EtiologyCell CycleCell Cycle ArrestCell ProliferationCell divisionCell physiologyChromatinChromosomal InstabilityChromosomal StabilityCleaved cellDNA DamageDNA RepairDevelopmentDrug DesignExcisionGenesGenome StabilityGenomic InstabilityGenotoxic StressGlioblastomaHumanIn VitroIndividualInheritedLeadLipidsMG132MaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of prostateMediatingMitosisMitoticMolecularMolecular AnalysisMolecular TargetMonoubiquitinationMusMutateMutationNormal CellNuclearNuclear ImportNuclear TranslocationPDPK1 genePTEN genePhosphatidylinositol 4,5-DiphosphatePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayPolyubiquitinationPost-Translational Protein ProcessingPredispositionProcessProtein KinaseRNA InterferenceRegulationReportingResearchRoleSecond Messenger SystemsSerineSignal PathwaySignal TransductionTailTestingThreonineTumor Suppressor ProteinsWorkangiogenesiscell growthdrug developmentin vitro Modelin vivointerestmalignant breast neoplasmmouse modelmulticatalytic endopeptidase complexphosphatidylinositol 3,4,5-triphosphatephosphatidylinositol 3,4-diphosphatesegregationtumortumorigenesisubiquitin-protein ligase
中文摘要
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。
英文摘要
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.
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会议论文
Chromatin PTEN: Its Regulation And Functions
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批准号:10200691
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资助金额:$38.35万
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依托单位:
Chromatin PTEN: Its Regulation And Functions
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