Regulation of the Hippo pathway and its role in uveal melanoma
Hippo通路的调节及其在葡萄膜黑色素瘤中的作用
基本信息
- 批准号:8529541
- 负责人:
- 金额:$ 36.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisBiochemicalBiologyCell CountCell ProliferationCell Surface ReceptorsCutaneous MelanomaDevelopmentDiseaseEyeFrequenciesG-Protein-Coupled ReceptorsGene ExpressionGeneticGenetic TranscriptionGoalsHumanKnowledgeLaboratoriesLigandsLiverLysophospholipidsMalignant NeoplasmsMammalian CellMolecularMutateMutationNeoplasm MetastasisOrgan SizePathway interactionsPhosphorylationPhosphotransferasesPlayProtein DephosphorylationProteinsRas/RafRegulationRoleSignal PathwaySignal TransductionSignaling MoleculeSphingosineStem cellsTestingTumor Suppressor ProteinsUveal Melanomabasecell motilityeffective therapyextracellularinsightlimitinlysophosphatidic acidself-renewalsphingosine 1-phosphatestemtherapeutic targettumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): The Hippo tumor suppressor pathway plays a crucial role in regulating organ size by inhibiting cell proliferation and promoting apoptosis, and limitin stem/progenitor cell self- renewal and expansion. The YAP/TAZ transcription co-activators are the major downstream effectors of the Hippo pathway. Despite extensive studies, upstream signals regulating the Hippo pathway are unknown. Currently, no extracellular ligand or cell surface receptor has been identified to regulate the mammalian Hippo-YAP. Our preliminary studies have discovered that lysophosphatidic acid (LPA) and sphingosine 1- phosphophate (S1P) are important signaling molecules that regulating the Hippo pathway. LPA and S1P act through their respective G-protein coupled receptors (GPCRs) to activate YAP. Both LPA and S1P have been implicated in cancer development and metastasis. Notably, activating mutations of Gq/11 are frequently found (83%) in uveal melanoma, which is the most common intraocular tumor in the eye with strong propensity of metastasis into the liver. Our preliminary study showed that active Gq/11 potently stimulates YAP activity. The major goals of this proposal are to investigate the mechanism of Hippo-YAP regulation by GPCR and to determine the functional significance of YAP/TAZ activation in the biology of LPA, S1P and other extracellular signals. Moreover, we will investigate the pathophysiological function of YAP/TAZ activation in the development of uveal melanoma and aim to provide scientific basis for treatment of this disease.
描述(由申请人提供):河马肿瘤抑制途径通过抑制细胞增殖和促进细胞凋亡,以及Limitin干/祖细胞的自我更新和扩增,在调节器官大小方面发挥关键作用。YAP/TAZ转录共激活子是河马途径的主要下游效应子。尽管进行了广泛的研究,但调节河马途径的上游信号尚不清楚。目前,还没有确定细胞外配体或细胞表面受体来调节哺乳动物的河马-YAP。我们的初步研究发现,溶血磷脂酸(LPA)和鞘氨醇1-磷酸(S1P)是调节河马信号通路的重要信号分子。LPA和S1P通过各自的G蛋白偶联受体(GPCRs)激活YAP。LPA和S1P都与肿瘤的发生和转移有关。值得注意的是,葡萄膜黑色素瘤中经常发现GQ/11的激活突变(83%),这是眼内最常见的肿瘤,有很强的肝脏转移倾向。我们的初步研究表明,活性的GQ/11有效地刺激了YAP的活性。本研究的主要目的是研究GPCR对Hippo-YAP的调控机制,并确定YAP/TAZ激活在LPA、S1P和其他细胞外信号生物学中的功能意义。此外,我们还将探讨YAP/TAZ激活在葡萄膜黑色素瘤发生发展中的病理生理作用,旨在为该病的治疗提供科学依据。
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(0)
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Kun-Liang Guan其他文献
Kun-Liang Guan的其他文献
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{{ truncateString('Kun-Liang Guan', 18)}}的其他基金
Functional interplay between Hippo and estrogen receptor ESR1
Hippo 和雌激素受体 ESR1 之间的功能相互作用
- 批准号:
10339901 - 财政年份:2022
- 资助金额:
$ 36.81万 - 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
- 批准号:
9453662 - 财政年份:2017
- 资助金额:
$ 36.81万 - 项目类别:
Molecular Mechanism and Therapy for Ocular Melanoma
眼部黑色素瘤的分子机制及治疗
- 批准号:
9328539 - 财政年份:2017
- 资助金额:
$ 36.81万 - 项目类别:
The mTOR and Hippo pathway in cell growth and cancer
mTOR 和 Hippo 通路在细胞生长和癌症中的作用
- 批准号:
9752481 - 财政年份:2015
- 资助金额:
$ 36.81万 - 项目类别:
The mTOR and Hippo pathway in cell growth and cancer
mTOR 和 Hippo 通路在细胞生长和癌症中的作用
- 批准号:
9120339 - 财政年份:2015
- 资助金额:
$ 36.81万 - 项目类别:
Regulation of the Hippo pathway and its role in uveal melanoma
Hippo通路的调节及其在葡萄膜黑色素瘤中的作用
- 批准号:
8722567 - 财政年份:2012
- 资助金额:
$ 36.81万 - 项目类别:
Regulation of the Hippo pathway and its role in uveal melanoma
Hippo通路的调节及其在葡萄膜黑色素瘤中的作用
- 批准号:
8340411 - 财政年份:2012
- 资助金额:
$ 36.81万 - 项目类别:
Protein phosphorylation and growth factor function
蛋白质磷酸化和生长因子功能
- 批准号:
7892688 - 财政年份:2009
- 资助金额:
$ 36.81万 - 项目类别:
Regulation and function of the YAP transcription co-activator oncoprotein
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- 批准号:
8022881 - 财政年份:2008
- 资助金额:
$ 36.81万 - 项目类别:
Regulation and function of the YAP transcription co-activator oncoprotein
YAP转录辅激活癌蛋白的调控和功能
- 批准号:
8627562 - 财政年份:2008
- 资助金额:
$ 36.81万 - 项目类别:
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