Erk pathway inhibitor U0126 induces gamma-globin expression in erythroid cells.
Fetal hemoglobin (HbF) induction is an effective approach to improve clinical symptoms in sickle cell disease. Understanding molecular mechanisms for gamma-gene re-activation will aid efforts to design lead compounds. A potential inhibitory role for the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway in gamma-gene expression has been suggested recently. Therefore, we determined the ability of U0126, a selective inhibitor of MEK1/2 the upstream activators of ERK, to re-activate gamma-globin expression. K562 stable lines over-expressing constitutively active MEK1 were established. A significant increase in ERK phosphorylation was observed and gamma-gene expression was silenced concomitantly, however U0126 attenuated this effect. Studies in human erythroid progenitors confirmed the ability of U0126 to induce HbF. Cellular mechanisms for the inhibitory role of ERK signaling in drug-mediated HbF induction will be discussed.
McElveen
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RL
Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083, USA.
Lou
T F
TF
Reese
K
K
Xia
S
S
Baliga
B S
BS
Pace
B S
BS
D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020014:K562 Cells; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D002070:Butadienes; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D005914:Globins; D005319:Fetal Hemoglobin; C482128:MAP2K2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human