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499846 
Journal Article 
ERK pathway inhibitor U0126 induces gamma-globin expression in erythroid cells 
Mcelveen, RL; Lou, TF; Reese, K; Xia, S; Baliga, BS; Pace, BS 
2005 
Yes 
Cellular and Molecular Biology
ISSN: 0145-5680
EISSN: 1165-158X 
Cell Mol Biol (Noisy-le-grand). 
51 
2 
215-227 
English 
10.1170/t621 
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. 
gamma-globin; fetal hemoglobin; sickle cell disease; U0126; ERK; signal-regulated kinases; p38 map kinase; activated protein-kinases; k562 leukemia-cells; gene-expression; fetal-hemoglobin; megakaryocytic; differentiation; histone deacetylase; in-vivo; constitutive activation