title: Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis.
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.
authors.affiliation: Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-2560, USA.
authors.forename: Wulin
authors.initials: W
authors.lastname: Aerbajinai
authors.forename: Jianqiong
authors.initials: J
authors.lastname: Zhu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Gao
authors.forename: Kyung
authors.initials: K
authors.lastname: Chin
authors.forename: Griffin P
authors.initials: GP
authors.lastname: Rodgers
mesh_terms: D000107:Acetylation; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013792:Thalidomide / Q000494:pharmacology*; D005719:gamma-Globulins / Q000187:drug effects* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D000975:Antioxidants; D006657:Histones; D017382:Reactive Oxygen Species; D005719:gamma-Globulins; D013792:Thalidomide; D048051:p38 Mitogen-Activated Protein Kinases