title: Systemic Reprogramming of Translation Efficiencies on Oxygen Stimulus.
abstract: Protein concentrations evolve under greater evolutionary constraint than mRNA levels. Translation efficiency of mRNA represents the chief determinant of basal protein concentrations. This raises a fundamental question of how mRNA and protein levels are coordinated in dynamic systems responding to physiological stimuli. This report examines the contributions of mRNA abundance and translation efficiency to protein output in cells responding to oxygen stimulus. We show that changes in translation efficiencies, and not mRNA levels, represent the major mechanism governing cellular responses to [O2] perturbations. Two distinct cap-dependent protein synthesis machineries select mRNAs for translation: the normoxic eIF4F and the hypoxic eIF4F(H). O2-dependent remodeling of translation efficiencies enables cells to produce adaptive translatomes from preexisting mRNA pools. Differences in mRNA expression observed under different [O2] are likely neutral, given that they occur during evolution. We propose that mRNAs contain translation efficiency determinants for their triage by the translation apparatus on [O2] stimulus.
authors: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: J J David
authors: JJD
authors: Ho
authors: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Miling
authors: M
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Timothy E
authors: TE
authors: Audas
authors: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Biostatistics and Bioinformatics Core, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Deukwoo
authors: D
authors: Kwon
authors: Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Steven K
authors: SK
authors: Carlsson
authors: Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: Sara
authors: S
authors: Timpano
authors: Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: Sonia L
authors: SL
authors: Evagelou
authors: Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Shaun
authors: S
authors: Brothers
authors: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Mark L
authors: ML
authors: Gonzalgo
authors: SPARC BioCentre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Jonathan R
authors: JR
authors: Krieger
authors: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Biostatistics and Bioinformatics Core, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Division of Biostatistics, Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 31336, USA.
authors: Steven
authors: S
authors: Chen
authors: Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors: James
authors: J
authors: Uniacke
authors: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 31336, USA; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: stephenlee@med.miami.edu.
authors: Stephen
authors: S
authors: Lee
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D039562:Eukaryotic Initiation Factor-4F; D012333:RNA, Messenger; D010100:Oxygen
keywords: HIF; RNA sequencing; SILAC; cancer; eIF4E; eIF4E2; eIF4F; hypoxia; oxygen; translation