Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis
阐明 LATS1/2 抑制肿瘤发生的新机制
基本信息
- 批准号:10357950
- 负责人:
- 金额:$ 16.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAutomobile DrivingAwardBasic ScienceBiochemicalBiological AssayBiological ProcessBreastBreast Cancer TreatmentCancer BiologyCancer DiagnosticsCell physiologyColorectalColorectal CancerDataDeubiquitinating EnzymeDeubiquitinationDevelopmentDrosophila genusEctopic ExpressionEndometrialEndometrial CarcinomaFamilyFamily memberFemale Breast CarcinomaFutureGenetic StatusGenetically Engineered MouseGliomaGoalsGrowthHumanIn VitroIndividualKnock-in MouseLATS1 geneLiverLungMalignant NeoplasmsMammalsMammary NeoplasmsMediatingMetabolismModificationMolecularMolecular and Cellular BiologyMouse Mammary Tumor VirusMusNatural regenerationNewly DiagnosedOncogenesOrgan SizeOrthologous GenePathway interactionsPhasePhosphorylationPhosphotransferasesPhysiologicalPolyubiquitinationProblem SolvingProcessProtein-Serine-Threonine KinasesProteinsRaptorsRegulationRoleScientistSignal PathwaySignal TransductionSiteTimeTissuesTrainingTranscription CoactivatorTranslational ResearchTumor Suppressor ProteinsUbiquitinationbasebreast tumorigenesiscancer therapycareercell growthdesigndruggable targetexperimental studyflyin vivoinsightmalignant breast neoplasmmammarynovelnovel therapeutic interventionnovel therapeuticsskillstargeted treatmenttumortumorigenesis
项目摘要
Abstract:
The Hippo pathway is an evolutionarily conserved signaling cascade regulating numerous biological processes,
including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in
mammals consists of a kinase cascade, LATS1/2 and MST1/2 that controls various cellular processes through
orchestrating the phosphorylation of downstream substrates including YAP and TAZ. In keeping with a
possible tumor suppressive role of the Hippo signaling pathway, it has been found that Hippo pathway
dysregulation is common in many human tumors including breast, glioma, lung, colorectal cancer, and
endometrial cancer. However, although a few of upstream regulators and downstream substrates were
identified, the exact molecular mechanisms underlying how upstream signaling pathways control LATS1/2
kinase activity and its physiological functions in breast cancer have not yet been fully elucidated. Hence, the
major goal of this proposal is to explore the upstream regulator of LATS1/2 as well as to uncover a novel tumor
suppressor role of LATS1/2 in controlling tumorigenesis in the breast cancer setting. To this end, I have
obtained preliminary data showing that the deubiquitinating enzyme OTUD3, but not other OTUD family
member, specifically interacts and deubiquitinates LATS1. More importantly, I identified Raptor, one of the core
components of mTORC1 which is a central cell growth regulator governing cellular metabolism, as a novel
phosphorylation substrate of LATS1/2. In this proposal, I plan to: 1) characterize OTUD3 as a novel upstream
regulator that positively regulates LATS1/2 kinase activity largely through deubiquitination of LATS1/2; 2)
determine the physiological role of LATS1/2 in suppressing breast tumorigenesis largely through
phosphorylating Raptor at Ser606 site, which in turn inhibits the kinase activity of mTORC1; 3) determine
whether and how Raptor phosphorylation at Ser606 by LATS1/2 regulates breast cancer development in vivo.
The long-term goals of my career are to apply the insights of molecular and cellular biology studies to
understand the physiological significance of deregulated Hippo/mTORC1 signaling pathways that are important
in the development of human malignancies, especially in breast cancer, and to search for proper druggable
targets for better anti-breast cancer treatment. This K99/R00 award will provide protected time for me to
pursue the novel hypotheses of this proposal, obtain new skill sets to execute experiments and solve problems.
In addition, the K99 award will allow me to focus my efforts on independently conducting basic and
translational research, and to train future young scientists in the cancer biology field.
摘要:
Hippo通路是一种进化上保守的信号级联,调节许多生物过程,
包括细胞生长和命运决定、器官大小控制和再生。河马途径的核心
哺乳动物由激酶级联、LATS 1/2和MST 1/2组成,其通过以下途径控制各种细胞过程:
协调下游底物包括雅普和TAZ的磷酸化。为了与A
Hippo信号通路可能的肿瘤抑制作用,已经发现Hippo通路
失调在许多人类肿瘤中是常见的,包括乳腺癌、神经胶质瘤、肺癌、结肠直肠癌,
子宫内膜癌然而,尽管一些上游调节子和下游底物被
确定了上游信号通路如何控制LATS 1/2的确切分子机制
激酶活性及其在乳腺癌中的生理功能尚未完全阐明。所以
该计划的主要目标是探索LATS 1/2的上游调节因子,并发现一种新的肿瘤
LATS 1/2在控制乳腺癌发生中的抑制作用。为此,我
获得的初步数据显示,去泛素化酶OTUD 3,而不是其他OTUD家族
成员,特别是相互作用和去泛素化LATS 1。更重要的是,我发现了猛禽,
mTORC 1是一种控制细胞代谢的中央细胞生长调节因子,
LATS 1/2的磷酸化底物。在这个提案中,我计划:1)将OTUD 3描述为一种新的上游
主要通过LATS 1/2的去泛素化正向调节LATS 1/2激酶活性的调节剂; 2)
确定LATS 1/2在抑制乳腺肿瘤发生中的生理作用,
在Ser 606位点磷酸化Raptor,这反过来抑制mTORC 1的激酶活性; 3)确定
LATS 1/2是否以及如何在Ser 606处磷酸化Raptor调节体内乳腺癌的发展。
我职业生涯的长期目标是将分子和细胞生物学研究的见解应用于
了解Hippo/mTORC 1信号通路失调的生理意义,
在人类恶性肿瘤的发展中,特别是在乳腺癌中,并寻找合适的药物
更好的抗乳腺癌治疗的目标。此K99/R 00奖励将为我提供受保护的时间,
追求这个提议的新假设,获得新的技能来执行实验和解决问题。
此外,K99奖将使我能够集中精力独立进行基本和
转化研究,并培养未来的年轻科学家在癌症生物学领域。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitochondrial PD-L1 modulates cancer immunotherapy.
线粒体 PD-L1 调节癌症免疫治疗。
- DOI:10.1038/s41422-023-00777-4
- 发表时间:2023
- 期刊:
- 影响因子:44.1
- 作者:Dai,Xiaoming;Liu,Jing;Wei,Wenyi
- 通讯作者:Wei,Wenyi
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{{ truncateString('Xiaoming Dai', 18)}}的其他基金
Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis
阐明 LATS1/2 抑制肿瘤发生的新机制
- 批准号:
10746905 - 财政年份:2021
- 资助金额:
$ 16.99万 - 项目类别:
Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis
阐明 LATS1/2 抑制肿瘤发生的新机制
- 批准号:
10191225 - 财政年份:2021
- 资助金额:
$ 16.99万 - 项目类别:
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