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Blood. 2007 Oct 15;110(8):2864-71. Epub 2007 Jul 9.

Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis.

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  • 1Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-2560, USA.

Abstract

Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thalidomide's specific effects on gamma-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on gamma-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34+ cells. We found that thalidomide induced gamma-globin mRNA expression in a dose-dependent manner, but had no effect on beta-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thalidomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced gamma-globin gene expression. These data indicate that thalidomide induces increased expression of the gamma-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation.

PMID:
17620452
[PubMed - indexed for MEDLINE]
PMCID:
PMC2018668
Free PMC Article
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