pSer784-VCP: a clinically relevant link between autophagy and DNA damage response
pSer784-VCP:自噬和 DNA 损伤反应之间的临床相关联系
基本信息
- 批准号:10435173
- 负责人:
- 金额:$ 22.09万
- 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:2022-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAffectAntibodiesAutophagocytosisAutophagosomeBiogenesisBiologicalBreast Cancer CellBreast Cancer PatientBreast Cancer cell lineBypassC-terminalCancer PatientCell LineCell NucleusCell SurvivalCellsChemoresistanceChemosensitizationChromatinClinicalCombined Modality TherapyCustomCytoplasmDNA DamageDNA RepairDataDependenceEtiologyEventFluorescenceGeneticGenome StabilityGrantHomeostasisHuman Cell LineKnowledgeLinkLysosomesMalignant NeoplasmsMammary NeoplasmsMediatingMethodsModelingMolecular ChaperonesMutagensNamesNuclearNuclear ExportOrganellesPathway interactionsPharmacologyPhosphorylationPhotobleachingPhysiologicalProcessPrognostic MarkerProteasome InhibitionProteinsReportingResistanceRoleSDZ RADSamplingSerumSignal TransductionSirolimusStainsStarvationStressTailTestingTherapeuticUbiquitinWorkcancer cellcancer therapychemosensitizing agentchemotherapychromatin proteinclinically relevantexperimental studygenotoxicityimprovedinhibitorinsightmTOR Inhibitormalignant breast neoplasmmimeticsmulticatalytic endopeptidase complexnovelprogramsrepairedresponsetherapeutically effectivetriple-negative invasive breast carcinoma
项目摘要
PROJECT SUMMARY
Autophagy and DNA damage response (DDR) are two evolutionarily conserved, fundamentally important
cellular programs. Both can be deregulated in cancer and in turn targeted as cancer therapies. Despite
compelling evidence that autophagy and DDR are connected, the scarce number of known DDR-relevant
autophagy targets greatly limits our understanding of their functional crosstalk. Mixed reports regarding the
chemotherapy-sensitizing effect of autophagy activation strongly suggest the context-dependency of the
physiological role of autophagy in DDR. We hypothesize that this context-dependency could be determined by
the functional importance of the affected autophagy targets for DDR. In this grant, we focus on an important
DDR factor named VCP. VCP is a ubiquitously expressed AAA+ ATPase which recognizes polyubiquitinated
proteins and facilitates their degradation by both the ubiquitin-proteasome and autophagy/lysosome pathways.
Our recent work showed that DNA damage-induced Ser784 phosphorylation selectively increases nuclear VCP
function for DDR. Importantly, pSer784-VCP is poor prognostic marker for chemotherapy-treated breast cancer
patients. These data suggest that targeting pSer784-VCP may be a novel and effective chemo-sensitizing
approach. In this grant, we present preliminary data showing that pSer784-VCP may be a previously
unrecognized target of autophagy. In Aim 1, we will define the specific autophagy pathway that is involved in
pSer784-VCP degradation and seek for direct evidence that pSer784-VCP undergoes nuclear export upon
DNA damage. In Aim 2, we will test in a large panel of triple-negative breast cancer cell lines whether DNA
damage-induced pSer784-VCP levels predict chemo-sensitizing effects of autophagy modulators. Together,
these experiments will improve our understanding of the functional crosstalk between autophagy and DDR,
and help define the biological context within which co-targeting of these two cellular programs can be
therapeutically beneficial.
项目总结
自噬和DNA损伤反应(DDR)是进化上保守的两个基本重要的
手机节目。这两种药物都可以在癌症中放松管制,进而作为癌症治疗的靶向。尽管
令人信服的证据表明,自噬和DDR是相关的,与DDR相关的已知数量很少
自噬目标极大地限制了我们对其功能串扰的理解。关于这一事件的报道褒贬不一
自噬激活的化疗增敏效应强烈地表明,
自噬在DDR中的生理作用。我们假设这种上下文依赖关系可以通过以下方式确定
受影响的DDR自噬靶标的功能重要性。在这笔赠款中,我们将重点放在一个重要的
DDR因子称为VCP。VCP是一种普遍表达的AAA+ATPase,它识别多泛素化
并通过泛素-蛋白酶体和自噬/溶酶体途径促进蛋白质的降解。
我们最近的工作表明,DNA损伤诱导的Ser784磷酸化选择性地增加了核VCP
用于DDR的函数。重要的是,pSer784-VCP是化疗后乳腺癌预后差的标志物
病人。这些数据表明,靶向pSer784-VCP可能是一种新的有效的化学增敏作用
接近。在这项研究中,我们提供了初步的数据,表明pSer784-VCP可能是以前的
无法识别的自噬目标。在目标1中,我们将定义特定的自噬途径,它涉及
PSer784-VCP降解并寻找pSer784-VCP经历核出口的直接证据
DNA损伤。在目标2中,我们将在一组三阴性的乳腺癌细胞系中测试DNA
损伤诱导的pSer784-VCP水平预测自噬调节剂的化学增敏效应。一起,
这些实验将提高我们对自噬和DDR之间的功能串扰的理解,
并帮助定义这两个细胞程序的共同靶向的生物学背景
对治疗有益。
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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Jieya Shao其他文献
Jieya Shao的其他文献
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{{ truncateString('Jieya Shao', 18)}}的其他基金
pSer784-VCP: a clinically relevant link between autophagy and DNA damage response
pSer784-VCP:自噬和 DNA 损伤反应之间的临床相关联系
- 批准号:
10612443 - 财政年份:2022
- 资助金额:
$ 22.09万 - 项目类别:
Understanding Spatially Regulated Tumor-Inhibitory Function of Profilin-1 and its Deregulation in Breast Cancer
了解 Profilin-1 的空间调节肿瘤抑制功能及其在乳腺癌中的失调
- 批准号:
10062480 - 财政年份:2016
- 资助金额:
$ 22.09万 - 项目类别:
Understanding Spatially Regulated Tumor-Inhibitory Function of Profilin-1 and its Deregulation in Breast Cancer
了解 Profilin-1 的空间调节肿瘤抑制功能及其在乳腺癌中的失调
- 批准号:
9239553 - 财政年份:2016
- 资助金额:
$ 22.09万 - 项目类别:
Role of nuclear profilin-1 in DNA replication fork stability and cancer chemotherapy response
核 profilin-1 在 DNA 复制叉稳定性和癌症化疗反应中的作用
- 批准号:
10587921 - 财政年份:2016
- 资助金额:
$ 22.09万 - 项目类别:
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