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Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome.
Ho, J J David; Cunningham, Tyler A; Manara, Paola; Coughlin, Caroline A; Arumov, Artavazd; Roberts, Evan R; Osteen, Ashanti; Kumar, Preet; Bilbao, Daniel; Krieger, Jonathan R; Lee, Stephen; Schatz, Jonathan H.
  • Ho JJD; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: dho@hexagonbio.com.
  • Cunningham TA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School
  • Manara P; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Coughlin CA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller
  • Arumov A; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Roberts ER; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Cancer Modeling Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Osteen A; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Cancer Modeling Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Kumar P; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Bilbao D; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Cancer Modeling Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Krieger JR; Bioinformatics Solutions Inc., Waterloo, ON N2L 6J2, Canada.
  • Lee S; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • Schatz JH; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: jschatz@med.miami.edu.
Cell Rep ; 37(2): 109806, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1466094
ABSTRACT
Tactical disruption of protein synthesis is an attractive therapeutic strategy, with the first-in-class eIF4A-targeting compound zotatifin in clinical evaluation for cancer and COVID-19. The full cellular impact and mechanisms of these potent molecules are undefined at a proteomic level. Here, we report mass spectrometry analysis of translational reprogramming by rocaglates, cap-dependent initiation disruptors that include zotatifin. We find effects to be far more complex than simple "translational inhibition" as currently defined. Translatome analysis by TMT-pSILAC (tandem mass tag-pulse stable isotope labeling with amino acids in cell culture mass spectrometry) reveals myriad upregulated proteins that drive hitherto unrecognized cytotoxic mechanisms, including GEF-H1-mediated anti-survival RHOA/JNK activation. Surprisingly, these responses are not replicated by eIF4A silencing, indicating a broader translational adaptation than currently understood. Translation machinery analysis by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) identifies rocaglate-specific dependence on specific translation factors including eEF1ε1 that drive translatome remodeling. Our proteome-level interrogation reveals that the complete cellular response to these historical "translation inhibitors" is mediated by comprehensive translational landscape remodeling.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Biosynthesis / Protein Synthesis Inhibitors Type of study: Experimental Studies / Prognostic study Limits: Animals / Humans / Male Language: English Journal: Cell Rep Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Biosynthesis / Protein Synthesis Inhibitors Type of study: Experimental Studies / Prognostic study Limits: Animals / Humans / Male Language: English Journal: Cell Rep Year: 2021 Document Type: Article