期刊
CANCER RESEARCH
卷 81, 期 15, 页码 4041-4053出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-3855
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资金
- Reynolds and Ryan Families Chair Fund of Translational Cancer
Valosin-containing protein (VCP) has been identified as a novel regulator of p53-R273H stability, stabilizing p53-R273H through binding to MDM2 and disrupting its association with mutant p53, while inhibition of VCP leads to ubiquitination and degradation of p53-R273H, promoting cell death. VCP may serve as a potential target for the development of pancreatic cancer therapy.
Approximately 80% of human pancreatic ductal adenocarcinomas (PDAC) harbor TP53 mutations, among which, R273H is the most frequent. Although p53-R273H is known to possess gain-of-function properties, how it is regulated in PDAC has not been extensively explored. Here we identify valosin-containing protein (VCP) as a regulator of p53-R273H by conducting immunoprecipitation-tandem mass spectrometry analysis. VCP hound p53R273H at its DNA binding domain. Ectopic or endogenous VCP stabilized p53-R273H by binding to MDM2 and disrupting its association with mutant p53. Inhibition of VCP either by genetic depletion or the pharmacologic inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy. Significance: These findings identify valosin-containing protein (VCP) as a novel regulator of p53-R273H stability and suggest VCP as a potential target for development of pancreatic cancer therapy.
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