Masatsugu Hiraki, So-Young Hwang, Shugeng Cao, Timothy R Ramadhar, Sanguine Byun, Kyoung Wan Yoon, Jung Hyun Lee, Kiki Chu, Aditi U Gurkar, Vihren Kolev, Jianming Zhang, Takushi Namba, Maureen E Murphy, David J Newman, Anna Mandinova, Jon Clardy, Sam W Lee
{"title":"通过p53- hsp40调控轴，突变型p53小分子再激活为野生型p53。","authors":"Masatsugu Hiraki, So-Young Hwang, Shugeng Cao, Timothy R Ramadhar, Sanguine Byun, Kyoung Wan Yoon, Jung Hyun Lee, Kiki Chu, Aditi U Gurkar, Vihren Kolev, Jianming Zhang, Takushi Namba, Maureen E Murphy, David J Newman, Anna Mandinova, Jon Clardy, Sam W Lee","doi":"10.1016/j.chembiol.2015.07.016","DOIUrl":null,"url":null,"abstract":"<p><p>TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2015-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.016","citationCount":"57","resultStr":"{\"title\":\"Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis.\",\"authors\":\"Masatsugu Hiraki, So-Young Hwang, Shugeng Cao, Timothy R Ramadhar, Sanguine Byun, Kyoung Wan Yoon, Jung Hyun Lee, Kiki Chu, Aditi U Gurkar, Vihren Kolev, Jianming Zhang, Takushi Namba, Maureen E Murphy, David J Newman, Anna Mandinova, Jon Clardy, Sam W Lee\",\"doi\":\"10.1016/j.chembiol.2015.07.016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.</p>\",\"PeriodicalId\":9772,\"journal\":{\"name\":\"Chemistry & biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2015-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.016\",\"citationCount\":\"57\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemistry & biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.chembiol.2015.07.016\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2015/8/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemistry & biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.chembiol.2015.07.016","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2015/8/27 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis.
TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.
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