Multiple physical stresses induce γ-globin gene expression and fetal hemoglobin production in erythroid cells. 2014

Emily K Schaeffer, and Rachel J West, and Sarah J Conine, and Christopher H Lowrey
Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Program in Experimental and Molecular Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.

Increased fetal hemoglobin (HbF) expression is beneficial for β-hemoglobinopathy patients; however, current inducing agents do not possess the ideal combination of efficacy, safety and ease of use. Better understanding the mechanisms involved in γ-globin gene induction is critical for designing improved therapies, as no complete mechanism for any inducing agent has been identified. Given the cytotoxic nature of most known inducing drugs, we hypothesized that γ-globin is a cell stress response gene, and that induction occurs via activation of cell stress signaling pathways. We tested this hypothesis by investigating the ability of physical stresses including heat-shock (HS), UV- and X-irradiation and osmotic shock to increase γ-globin gene expression in erythroid cells. Experiments in K562 and KU812 cells showed that each of these stresses increased steady-state γ-globin mRNA levels, but only after 3-5days of treatments. HS and UV also increased γ-globin mRNA and HbF levels in differentiating primary human erythroid cells. Mechanistic studies showed that HS affects γ-globin mRNA at multiple levels, including nascent transcription and transcript stability, and that induction is dependent on neither the master regulator of the canonical HS response, HSF1, nor p38 MAPK. Inhibitor panel testing identified PI3K inhibitor LY294002 as a novel inducing agent and revealed potential roles for NFκB and VEGFR/PDGFR/Raf kinases in HS-mediated γ-globin gene induction. These findings suggest that cell stress signaling pathways play an important role in γ-globin gene induction and may provide novel targets for the pharmacologic induction of fetal hemoglobin.

UI MeSH Term Description Entries
D009997 Osmotic Pressure The pressure required to prevent the passage of solvent through a semipermeable membrane that separates a pure solvent from a solution of the solvent and solute or that separates different concentrations of a solution. It is proportional to the osmolality of the solution. Osmotic Shock,Hypertonic Shock,Hypertonic Stress,Hypotonic Shock,Hypotonic Stress,Osmotic Stress,Hypertonic Shocks,Hypertonic Stresses,Hypotonic Shocks,Hypotonic Stresses,Osmotic Pressures,Osmotic Shocks,Osmotic Stresses,Pressure, Osmotic,Pressures, Osmotic,Shock, Hypertonic,Shock, Hypotonic,Shock, Osmotic,Shocks, Hypertonic,Shocks, Hypotonic,Shocks, Osmotic,Stress, Hypertonic,Stress, Hypotonic,Stress, Osmotic,Stresses, Hypertonic,Stresses, Hypotonic,Stresses, Osmotic
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D004920 Erythropoiesis The production of red blood cells (ERYTHROCYTES). In humans, erythrocytes are produced by the YOLK SAC in the first trimester; by the liver in the second trimester; by the BONE MARROW in the third trimester and after birth. In normal individuals, the erythrocyte count in the peripheral blood remains relatively constant implying a balance between the rate of erythrocyte production and rate of destruction. Erythropoieses
D005319 Fetal Hemoglobin The major component of hemoglobin in the fetus. This HEMOGLOBIN has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by LEUKEMIA and several types of ANEMIA. Hemoglobin F,Hemoglobin, Fetal
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006358 Hot Temperature Presence of warmth or heat or a temperature notably higher than an accustomed norm. Heat,Hot Temperatures,Temperature, Hot,Temperatures, Hot
D006453 Hemoglobinopathies A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. Hemoglobinopathy
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000076249 Heat Shock Transcription Factors Heat and cold stress-inducible, transcription factors that bind to inverted 5'-NGAAN-3' pentamer DNA sequences and are regulated by POLY-ADP-RIBOSYLATION. They play essential roles as transcriptional activators of the HEAT-SHOCK RESPONSE by inducing expression of large classes of MOLECULAR CHAPERONES and heat-shock proteins. They also function in DNA REPAIR; transcriptional reactivation of latent HIV-1; and pre-mRNA processing and nuclear export of HSP70 HEAT-SHOCK PROTEINS during heat stress. Heat Stress Transcription Factor,Plant Heat Shock Factor,Heat Shock Factor Protein 1,Heat Shock Factor, Plant,Heat Shock Transcription Factor,Heat Shock Transcription Factor 1,Heat Stress Transcription Factors,Plant Heat Shock Factors

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