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) mi...

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Bibliographic Details
Published in:	Cellular and Molecular Biology Vol. 51; no. 2; p. 215
Main Authors:	McElveen, R L, Lou, T F, Reese, K, Xia, S, Baliga, B S, Pace, B S
Format:	Journal Article
Language:	English
Published:	France 05-09-2005
Subjects:	Blotting, Western Butadienes - pharmacology Cell Death - drug effects Cell Proliferation - drug effects Enzyme Inhibitors - pharmacology Erythroid Precursor Cells - drug effects Erythroid Precursor Cells - metabolism Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases - metabolism Fetal Hemoglobin - biosynthesis Fetal Hemoglobin - genetics Gene Expression Regulation - drug effects Globins - biosynthesis Globins - genetics Histone Deacetylase Inhibitors Humans K562 Cells MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - metabolism MAP Kinase Kinase 2 - antagonists & inhibitors MAP Kinase Kinase 2 - metabolism Nitriles - pharmacology Phosphorylation Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - biosynthesis RNA, Messenger - genetics Signal Transduction - drug effects Signal Transduction - physiology
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0145-5680 1165-158X
DOI:	10.1170/T621