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Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation.
Wu, H Helena; Wang, Benfan; Armstrong, Stephen R; Abuetabh, Yasser; Leng, Sarah; Roa, Wilson H Y; Atfi, Azeddine; Marchese, Adriano; Wilson, Beverly; Sergi, Consolato; Flores, Elsa R; Eisenstat, David D; Leng, Roger P.
Afiliação
  • Wu HH; 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
  • Wang B; 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
  • Armstrong SR; 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
  • Abuetabh Y; 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
  • Leng S; 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
  • Roa WHY; Department of Oncology, Cross Cancer Institute, 11560 University Ave., University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
  • Atfi A; Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.
  • Marchese A; Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave., Maywood, IL 60153, USA.
  • Wilson B; Department of Pediatrics, University of Alberta, 11405 - 87 Ave., Edmonton, Alberta T6G 1C9, Canada.
  • Sergi C; Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada.
  • Flores ER; Department of Molecular Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
  • Eisenstat DD; Department of Oncology, Cross Cancer Institute, 11560 University Ave., University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
  • Leng RP; Department of Pediatrics, University of Alberta, 11405 - 87 Ave., Edmonton, Alberta T6G 1C9, Canada.
Nucleic Acids Res ; 49(5): 2740-2758, 2021 03 18.
Article em En | MEDLINE | ID: mdl-33619536
The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas de Choque Térmico HSP70 / Proteínas Supressoras de Tumor / Ubiquitina-Proteína Ligases / Ubiquitinação Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas de Choque Térmico HSP70 / Proteínas Supressoras de Tumor / Ubiquitina-Proteína Ligases / Ubiquitinação Idioma: En Ano de publicação: 2021 Tipo de documento: Article