| Literature DB >> 26320861 |
Masatsugu Hiraki1, So-Young Hwang1, Shugeng Cao2, Timothy R Ramadhar3, Sanguine Byun1, Kyoung Wan Yoon1, Jung Hyun Lee1, Kiki Chu1, Aditi U Gurkar1, Vihren Kolev1, Jianming Zhang1, Takushi Namba1, Maureen E Murphy4, David J Newman5, Anna Mandinova6, Jon Clardy7, Sam W Lee8.
Abstract
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.Entities:
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Year: 2015 PMID： 26320861 PMCID： PMC4670040 DOI： 10.1016/j.chembiol.2015.07.016
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521