Decoding the MST1 and MST2 kinases in cellular physiology and tumor suppression
解码细胞生理学和肿瘤抑制中的 MST1 和 MST2 激酶
基本信息
- 批准号:8450270
- 负责人:
- 金额:$ 57.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-06 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAdultApoptosisBiochemicalCaspaseCatalytic DomainCell ProliferationCell physiologyCellsCleaved cellClinicalComplexDataDefectDevelopmentDiseaseDrosophila genusElementsExcisionExhibitsFamilyGenerationsGeneticGrowthGuanosine Triphosphate PhosphohydrolasesHepaticHepatocyteHumanIn VitroLiverMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of liverMammalian CellMammalsMediatingMolecularMusNuclearOncogenesOrgan SizeOrthologous GeneOutputPathogenesisPathway interactionsPhosphorylationPhosphotransferasesPhysiologicalPrimary carcinoma of the liver cellsProtein KinaseRegulationResistanceRoleSeriesSignal PathwaySignal TransductionSpecimenT-LymphocyteTherapeuticTranscription CoactivatorTumor SuppressionTumor Suppressor GenesTumor Suppressor Proteinsbasecarcinogenesisflyhuman FRAP1 proteinimprovedin vivoinsightmolecular phenotypenoveloverexpressionpolypeptidepublic health relevancereceptorresearch studyresidenceresponsetherapeutic targettumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): We have recently identified the Mst1/2 ser/thr kinases as important hepatocellular carcinoma (HCC) tumor suppressors. Mst1/2 are the orthologs of the Drosophila tumor suppressor Hippo, which promotes apoptosis and inhibits cell proliferation during development. Hippo action is mediated by a set of critical substrates which are conserved in humans, and which in turn suppress the transcriptional coactivator, Yorkie, whose human ortholog, Yap, is an established oncogene and regulator of organ size. By generating Mst1/2 KO mice we found that Mst1 and Mst2 are required to maintain quiescence of liver cells and that their liver-specific ablation results in Yap activation, liver overgrowth, resistance to apoptosis, and the rapid development of HCC. Significantly, we have determined that ~30% of human HCCs have deregulation of the Mst1/2-Yap signaling axis. These results establish Mst1/2 as important tumor suppressors relevant to the pathogenesis of HCC in humans and point to Yap as one critical downstream target. Although Mst1/Mst2 lie at the center of an important growth control network, much about the physiologic regulation and functions of Mst1/2 and their role as tumor suppressors remains to be determined. We find that the upstream regulation and outputs of Mst1 and Mst2 in mammalian cells differ markedly from those predicted by the Drosophila Hippo pathway and by in vitro overexpression studies. In murine naive T cells, e.g., Mst1/2 negatively regulate proliferation independently of Yap. Moreover Mst1/2 are constitutive partners of the Rassf family of tumor suppressor polypeptides, some of which (e.g., Nore1/Rassf5) are regulated by Ras-like GTPases. Which of these multiple upstream elements control Mst1/Mst2 in liver is an open question. This proposal describes a systematic approach to define in molecular terms the upstream regulatory inputs and critical outputs of Mst1/2 that determine the capacity of Mst1/2 to regulate liver growth and exert tumor suppression in vivo. The regulation of Yap and its contribution to carcinogenesis will be investigated in detail. We have also identified Yap- independent responses to Mst1/2 deficiency, whose mechanism of activation and contribution to the malignant transformation of hepatocytes will be determined. Finally we will characterize the human HCCs that exhibit deregulation of the Mst1/Mst2 pathway, and determine how such deregulation influences the histopathologic and clinical features of human HCC. These studies are likely to reveal new strategies for the therapy of HCC and as well as of other human cancers that have defective regulation of the Mst1/2 kinases.
描述(由申请人提供):我们最近发现Mst 1/2 ser/thr激酶是重要的肝细胞癌(HCC)肿瘤抑制因子。Mst 1/2是果蝇肿瘤抑制因子Hippo的直系同源物,其在发育期间促进细胞凋亡并抑制细胞增殖。河马的作用是由一组关键底物介导的,这些底物在人类中是保守的,并且反过来抑制转录辅激活因子Yorkie,Yorkie的人类直系同源物雅普是一种已确定的致癌基因和器官大小的调节因子。通过产生Mst 1/2 KO小鼠,我们发现Mst 1和Mst 2是维持肝细胞静止所必需的,并且它们的肝脏特异性消融导致雅普激活、肝脏过度生长、抗凋亡和HCC的快速发展。值得注意的是,我们已经确定约30%的人HCC具有Mst 1/2-雅普信号传导轴的失调。这些结果证实Mst 1/2是与人类HCC发病机制相关的重要肿瘤抑制因子,并指出雅普是一个关键的下游靶点。虽然Mst 1/Mst 2位于重要的生长控制网络的中心,但关于Mst 1/2的生理调节和功能及其作为肿瘤抑制剂的作用仍有待确定。我们发现,在哺乳动物细胞中的MST 1和MST 2的上游调控和输出显着不同的果蝇河马途径和体外过表达研究所预测的。在小鼠幼稚T细胞中,例如,Mst 1/2独立于雅普负调控增殖。此外,Mst 1/2是肿瘤抑制多肽的Rassf家族的组成型配偶体,其中一些(例如,Nore1/Rassf5)受Ras样GTP酶调节。这些多个上游元件中的哪一个控制肝脏中的Mst 1/Mst 2是一个悬而未决的问题。该提案描述了一种系统的方法来定义在分子方面的上游调控输入和Mst 1/2的关键输出,确定Mst 1/2的能力,以调节肝脏生长和发挥体内肿瘤抑制。雅普的调节及其对致癌作用的贡献将被详细研究。我们还确定了雅普-独立的Mst 1/2缺陷的反应,其激活机制和肝细胞恶性转化的贡献将被确定。最后,我们将描述人类肝癌表现出失调的Mst 1/Mst 2通路,并确定这种失调如何影响人类肝癌的组织病理学和临床特征。这些研究有可能揭示治疗HCC以及其他Mst 1/2激酶调节缺陷的人类癌症的新策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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JOSEPH AVRUCH其他文献
JOSEPH AVRUCH的其他文献
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{{ truncateString('JOSEPH AVRUCH', 18)}}的其他基金
Decoding the MST1 and MST2 kinases in cellular physiology and tumor suppression
解码细胞生理学和肿瘤抑制中的 MST1 和 MST2 激酶
- 批准号:
8105217 - 财政年份:2010
- 资助金额:
$ 57.48万 - 项目类别:
Decoding the MST1 and MST2 kinases in cellular physiology and tumor suppression
解码细胞生理学和肿瘤抑制中的 MST1 和 MST2 激酶
- 批准号:
7984806 - 财政年份:2010
- 资助金额:
$ 57.48万 - 项目类别:
The Boston Area Diabetes Endocrinology Research Center
波士顿地区糖尿病内分泌研究中心
- 批准号:
8063421 - 财政年份:2010
- 资助金额:
$ 57.48万 - 项目类别:
Decoding the MST1 and MST2 kinases in cellular physiology and tumor suppression
解码细胞生理学和肿瘤抑制中的 MST1 和 MST2 激酶
- 批准号:
8244374 - 财政年份:2010
- 资助金额:
$ 57.48万 - 项目类别:
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