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：
Jieya Shao
金额：
$ 22.09万
依托单位：
WASHINGTON UNIVERSITY
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：
https://reporter.nih.gov/project-details/10435173
关键词：
ATP phosphohydrolase Affect Antibodies Autophagocytosis Autophagosome Biogenesis Biological Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Bypass C-terminal Cancer Patient Cell Line Cell Nucleus Cell Survival Cells Chemoresistance Chemosensitization Chromatin Clinical Combined Modality Therapy Custom Cytoplasm DNA Damage DNA Repair Data Dependence Etiology Event Fluorescence Genetic Genome Stability Grant Homeostasis Human Cell Line Knowledge Link Lysosomes Malignant Neoplasms Mammary Neoplasms Mediating Methods Modeling Molecular Chaperones Mutagens Names Nuclear Nuclear Export Organelles Pathway interactions Pharmacology Phosphorylation Photobleaching Physiological Process Prognostic Marker Proteasome Inhibition Proteins Reporting Resistance Role SDZ RAD Sampling Serum Signal Transduction Sirolimus Stains Starvation Stress Tail Testing Therapeutic Ubiquitin Work cancer cell cancer therapy chemosensitizing agent chemotherapy chromatin protein clinically relevant experimental study genotoxicity improved inhibitor insight mTOR Inhibitor malignant breast neoplasm mimetics multicatalytic endopeptidase complex novel programs repaired response therapeutically effective triple-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.

项目摘要自噬和DNA损伤反应（DDR）是两个进化保守的，根本重要蜂窝程序。两者都可以在癌症中放松管制，进而将其作为癌症疗法。尽管令人信服的证据表明自噬和DDR连接，已知的DDR相关的稀缺数量自噬的目标极大地限制了我们对其功能串扰的理解。关于自噬激活的化学疗法敏感性强烈表明了上下文依赖性自噬在DDR中的生理作用。我们假设这种上下文依赖性可以由受影响的自噬目标对DDR的功能重要性。在这笔赠款中，我们专注于重要的 DDR因子名为VCP。 VCP是一种普遍表达的AAA+ ATPase，识别为多泛素化蛋白质并通过泛素 - 蛋白酶体和自噬/溶酶体途径来促进它们的降解。我们最近的工作表明，DNA损伤诱导的Ser784磷酸化有选择地增加了核VCP DDR的功能。重要的是，PSER784-VCP对于化学疗法治疗的乳腺癌的预后标志很差患者。这些数据表明，针对PSER784-VCP可能是一种新颖而有效的化学敏化方法。在这笔赠款中，我们提供了初步数据，表明PSER784-VCP可能是先前的自噬的无法识别的靶标。在AIM 1中，我们将定义所涉及的特定自噬途径 PSER784-VCP降解并寻求直接证据表明PSER784-VCP在 DNA损伤。在AIM 2中，我们将在大型三阴性乳腺癌细胞系中进行测试是否DNA 损伤引起的PSER784-VCP水平预测自噬调节剂的化学敏化作用。一起，这些实验将提高我们对自噬和DDR之间功能串扰的理解，并有助于定义这两个蜂窝程序的共同定位的生物学环境治疗上有益。