A novel cilium-to-nucleus axis promotes cellular senescence
一种新的纤毛到细胞核轴促进细胞衰老
基本信息
- 批准号:10414471
- 负责人:
- 金额:$ 32.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ARL3 geneAbbreviationsAcute Promyelocytic LeukemiaAddressAdenosine DiphosphateAffectAgeAgingAnimal ModelAnimalsApoptosisArchitectureBindingBinding ProteinsBiogenesisBiologyBromodomainCell AgingCell NucleusCellsCellular StressCiliaClinicCuesCultured CellsDataDevicesDiseaseEmbryonic DevelopmentEnzymesEpithelial CellsEukaryotic CellExhibitsFiberFibroblastsFunctional disorderGeneticGoalsGrowthGrowth FactorGuanosine Triphosphate PhosphohydrolasesHeterogeneityHomeostasisHumanHuman bodyInflammatoryJoubert syndromeLifeLinkLongevityMalignant NeoplasmsMammalian CellModelingModificationMolecularMusMutateNuclearNuclear ProteinNuclear StructureOrganPathogenesisPathologyPathway interactionsPeptide HydrolasesPharmacologyPhysiologicalPlayProteinsProteomicsRadiationRegulationResourcesRodent ModelRoleSeminalSensorySignal TransductionSomatic CellStressStructureSumoylation PathwaySurfaceSyndromeTP53 geneTherapeuticTissuesTumor SuppressionUbiquitinUp-Regulationagedbasechemokineciliopathycilium biogenesiscomorbiditycytokinedesignfrailtyhealthspanhealthy agingimprovedin vivoin vivo Modelirradiationmouse modelnovelnovel strategiesnovel therapeuticsoverexpressionp53-binding protein 1preventprogramsresponsesenescencetranscription factor PMLtumorigenesis
项目摘要
Project Summary
Cellular senescence is a programmed growth arrest activated by irreparable extrinsic or intrinsic stresses.
Senescence can be beneficial in certain circumstances, such as tissue homeostasis during embryonic
development or tumor suppression. However, if persistently secreted by senescent cells, the proinflammatory
cytokines, chemokines, proteases, and growth factors are actually major drivers for aging and age-associated
diseases and, paradoxically, promote tumorigenesis. Genetic or pharmacological clearance of senescent cells
effectively improves lifespan and healthspan in rodent models. As such, targeting senescence has emerged as
a promising therapeutic strategy to prevent or treat aging comorbidities and cancer. However, how the
irreversible senescence program is induced and maintained in stressed cells remains poorly understood.
Cells utilize primary cilia to convert environmental cues into diverse cellular signalings that govern
proliferation, differentiation, and tissue homeostasis. Cilia dysfunction leads to a wide spectrum of syndromic
disorders that are collectively termed ciliopathies. Using irradiation, we discovered that stressed human
fibroblasts or epithelial cells exhibit transient cilia biogenesis. Strikingly, FBF1, a component of transition fibers
(TFs) at the ciliary base, unexpectedly translocates to promyelocytic leukaemia nuclear bodies (PML-NBs) in
stressed cells. PML-NBs are highly dynamic proteinaceous nuclear structures with instrumental roles in
regulating stress-induced responses, including senescence and apoptosis. FBF1 depletion effectively
abolishes stress-induced PML-NB upregulation and associated senescence initiation, whereas FBF1
overexpression shows the opposite effects. Our initial studies indicated that the stress-induced PML-NB
translocation of FBF1 is regulated by a distinct cilia module comprising Joubert syndrome proteins ARL3 and
ARL13B and the SUMO-conjugating enzyme UBC9. Further proteomic studies revealed novel FBF1
interactors (PML, 53BP1, and BRD4) implicated in PML-NB biogenesis and/or function. Remarkably,
Fbf1tm1a/tm1a mice exhibit a significantly reduced senescence burden throughout life and could be further
protected against irradiation-induced frailty. Our preliminary data thus suggest an exciting paradigm that a
stress-induced TF-to-PML-NB translocation of ciliary protein FBF1 is essential for senescence
initiation in mammalian cells. Here, we propose to use complementary approaches to address mechanistic
questions, including how the ciliary ARL3-ARL13B-UBC9 module regulates FBF1 SUMOylation and PML-NB
translocation (Aim 1), and how PML-NB-associated FBF1 promotes senescence in stressed cells (Aim 2).
Together with the extended analysis of the physiological importance of FBF1 pathway in in vivo senescence
mouse models (Aim 3), this project will potentially bridge the fundamental discovery to the next generation of
therapeutic strategies for preventing or treating senescence-associated pathologies.
项目总结
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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{{ truncateString('Jinghua Hu', 18)}}的其他基金
A novel cilium-to-nucleus axis promotes cellular senescence
一种新的纤毛到细胞核轴促进细胞衰老
- 批准号:
10627992 - 财政年份:2022
- 资助金额:
$ 32.6万 - 项目类别:
Exploration of the functions of the ciliopathy Arls in cilia
纤毛病Arls在纤毛中的功能探讨
- 批准号:
9204826 - 财政年份:2016
- 资助金额:
$ 32.6万 - 项目类别:
Exploration of the functions of the ciliopathy Arls in cilia.
纤毛病 Arls 在纤毛中的功能探索。
- 批准号:
8019251 - 财政年份:2011
- 资助金额:
$ 32.6万 - 项目类别:
Exploration of the functions of the ciliopathy Arls in cilia.
纤毛病 Arls 在纤毛中的功能探索。
- 批准号:
8212390 - 财政年份:2011
- 资助金额:
$ 32.6万 - 项目类别:
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