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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.

项目总结