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Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis.
Hiraki, Masatsugu; Hwang, So-Young; Cao, Shugeng; Ramadhar, Timothy R; Byun, Sanguine; Yoon, Kyoung Wan; Lee, Jung Hyun; Chu, Kiki; Gurkar, Aditi U; Kolev, Vihren; Zhang, Jianming; Namba, Takushi; Murphy, Maureen E; Newman, David J; Mandinova, Anna; Clardy, Jon; Lee, Sam W.
Affiliation
  • Hiraki M; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Hwang SY; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Cao S; Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Ramadhar TR; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Byun S; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Yoon KW; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Lee JH; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Chu K; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Gurkar AU; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Kolev V; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Zhang J; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Namba T; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • Murphy ME; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.
  • Newman DJ; Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • Mandinova A; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Clardy J; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jon_clardy@hms.harvard.edu.
  • Lee SW; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: swlee@mgh.harvard.edu.
Chem Biol ; 22(9): 1206-16, 2015 Sep 17.
Article in En | MEDLINE | ID: mdl-26320861
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tumor Suppressor Protein p53 / Indole Alkaloids / Disulfides / HSP40 Heat-Shock Proteins / Small Molecule Libraries / Antineoplastic Agents Limits: Animals / Humans Language: En Journal: Chem Biol Journal subject: BIOLOGIA / BIOQUIMICA / QUIMICA Year: 2015 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tumor Suppressor Protein p53 / Indole Alkaloids / Disulfides / HSP40 Heat-Shock Proteins / Small Molecule Libraries / Antineoplastic Agents Limits: Animals / Humans Language: En Journal: Chem Biol Journal subject: BIOLOGIA / BIOQUIMICA / QUIMICA Year: 2015 Document type: Article Affiliation country: United States