title: Induction of fetal hemoglobin through enhanced translation efficiency of γ-globin mRNA.
abstract: Fetal hemoglobin (HbF) induction can ameliorate the clinical severity of sickle cell disease and β-thalassemia. We previously reported that activation of the eukaryotic initiation factor 2α (eIF2α) stress pathway increased HbF through a posttranscriptional mechanism. In this study, we explored the underlying means by which salubrinal, an activator of eIF2α signaling, enhances HbF production in primary human erythroid cells. Initial experiments eliminated changes in globin messenger RNA (mRNA) stability or cellular location and reduction of adult hemoglobin as possible salubrinal mechanisms. We then determined that salubrinal selectively increased the number of actively translating ribosomes on γ-globin mRNA. This enhanced translation efficiency occurred in the recovery phase of the stress response as phosphorylation of eIF2α and global protein synthesis returned toward baseline. These findings highlight γ-globin mRNA translation as a novel mechanism for regulating HbF production and as a pharmacologic target for induction of HbF.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH; and.
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Hahn
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH; and Department of Medicine, and Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lowrey
mesh_terms: D015153:Blotting, Western; D002934:Cinnamates / Q000494:pharmacology; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D055545:gamma-Globins; C496827:salubrinal; D005319:Fetal Hemoglobin; D013890:Thiourea