PTEN and Cancer
PTEN 与癌症
基本信息
- 批准号:10227679
- 负责人:
- 金额:$ 101.2万
- 依托单位:
- 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:2017-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteBindingC2 DomainCancer PatientCell ProliferationCellsCellular Metabolic ProcessDNA biosynthesisExcisionGlucoseGlycolysisGoalsGrowthGuanosine TriphosphateHumanInsulin Signaling PathwayMalignant NeoplasmsMetabolic PathwayMusMutateNormal CellOncogenicPDPK1 genePH DomainPTEN genePhosphoric Monoester HydrolasesPhosphotransferasesPhysiologyProtein IsoformsProto-Oncogene Proteins c-aktRegulationResearchRoleSignal TransductionTissuesTumor Suppressor GenesTumor Suppressor Proteinsbasecancer cellcancer therapycell growthglucose uptakehuman diseaseimprovedinsightmigrationneoplastic cellphosphatidylinositol 3-phosphateprogramstumortumor initiationtumor progression
项目摘要
PTEN is one of the most frequently mutated tumor suppressors in human cancer, and effective approaches for
treating cancer with PTEN alteration is needed. Inactivation of PTEN cooperates with different oncogenic
signals to stimulate tumor initiation and progression and can be mutated in early or advanced human disease.
Though two hit inactivation is more penetrant than one hit for PTEN in mice, partial inactivation via
haploinsufficiency is sufficient to cause tumor progression. Much of PTEN’s tumor suppressor function can be
attributed to its role as a negative regulator of PI3K signaling by virtue of its ability to act as a phosphatase that
catalyzes the removal of the D-3 phosphate from phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 binds
the PH domain of AKT kinase and the PH domains of two PIP3-regulated kinases PDK1 and mTORC2, which
coordinately phosphorylate AKT to activate it. PIP3 in parallel binds the PH domains of PREX1 and PREX2 to
stimulate GTP loading of RAC1. The parallel PIP3-dependent activation of AKT and RAC coordinate the
activation of glycolysis in the cell, and under these conditions AKT activates mTORC1. Tumors that lack PTEN
have elevated PIP3 with increased AKT, TORC1, and RAC signaling, increased DNA replication and up
regulated metabolic pathways involved in cell growth. In normal physiology, PTEN is a key negative regulator
of the insulin signaling pathway, and loss of PTEN leads to increased glucose uptake in different tissues of the
body. Acute inactivation of PTEN in normal cells leads to increased cellular PIP3 and glucose flux
accompanied by increased proliferation, migration, and survival. The PTEN locus encodes multiple isoforms of
PTEN, including the recently identified PTEN-L, which share common phosphatase and C2 domains. My
research program focuses on the PTEN tumor suppressor. In this proposal, the broad scientific question that I
will ask is: what are the tumor suppressor functions of PTEN and PTEN-L and how are they regulated? The
goals of this application are to define mechanisms of PTEN regulation, determine the consequences of
inactivation in tissue and on cell proliferation and metabolism, and to develop approaches for targeting tumor
cells based upon their PTEN status. I expect that greater understanding of PTEN’s inactivation and regulation
will lead to improved therapy for cancer.
PTEN是人类肿瘤中最常见的突变肿瘤抑制因子之一,也是治疗肿瘤的有效途径
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Ramon E Parsons其他文献
Ramon E Parsons的其他文献
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{{ truncateString('Ramon E Parsons', 18)}}的其他基金
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
蒂施癌症研究所 - 癌症中心支持拨款
- 批准号:
10674487 - 财政年份:2015
- 资助金额:
$ 101.2万 - 项目类别:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
蒂施癌症研究所 - 癌症中心支持拨款
- 批准号:
10229103 - 财政年份:2015
- 资助金额:
$ 101.2万 - 项目类别:
The Tisch Cancer Institute - Cancer Center Support Grant
蒂施癌症研究所 - 癌症中心支持补助金
- 批准号:
9753966 - 财政年份:2015
- 资助金额:
$ 101.2万 - 项目类别:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
蒂施癌症研究所 - 癌症中心支持拨款
- 批准号:
10293870 - 财政年份:2015
- 资助金额:
$ 101.2万 - 项目类别:
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