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KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism.
Vaseva, Angelina V; Blake, Devon R; Gilbert, Thomas S K; Ng, Serina; Hostetter, Galen; Azam, Salma H; Ozkan-Dagliyan, Irem; Gautam, Prson; Bryant, Kirsten L; Pearce, Kenneth H; Herring, Laura E; Han, Haiyong; Graves, Lee M; Witkiewicz, Agnieszka K; Knudsen, Erik S; Pecot, Chad V; Rashid, Naim; Houghton, Peter J; Wennerberg, Krister; Cox, Adrienne D; Der, Channing J.
Afiliación
  • Vaseva AV; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • Blake DR; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Gilbert TSK; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Ng S; Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • Hostetter G; Pathology and Biorepository Core, The Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • Azam SH; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Ozkan-Dagliyan I; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Gautam P; Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
  • Bryant KL; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Pearce KH; Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Herring LE; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Han H; Molecular Medicine Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  • Graves LM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Witkiewicz AK; Center for Personalized Medicine, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • Knudsen ES; Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY 14203, USA.
  • Pecot CV; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, University of North Carolina at Chapel Hill,
  • Rashid N; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Houghton PJ; The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • Wennerberg K; Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
  • Cox AD; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel H
  • Der CJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel H
Cancer Cell ; 34(5): 807-822.e7, 2018 11 12.
Article en En | MEDLINE | ID: mdl-30423298
ABSTRACT
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3ß signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogénicas p21(ras) / Proteínas Proto-Oncogénicas c-myc / Proteína Quinasa 1 Activada por Mitógenos / Carcinoma Ductal Pancreático / MAP Quinasa Quinasa 5 / Proteína Quinasa 3 Activada por Mitógenos / Proteína Quinasa 7 Activada por Mitógenos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Proteínas Proto-Oncogénicas p21(ras) / Proteínas Proto-Oncogénicas c-myc / Proteína Quinasa 1 Activada por Mitógenos / Carcinoma Ductal Pancreático / MAP Quinasa Quinasa 5 / Proteína Quinasa 3 Activada por Mitógenos / Proteína Quinasa 7 Activada por Mitógenos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos