title: Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons.
abstract: Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.
authors.affiliation: Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering, South Korea.
authors.forename: Hye-Ryeong
authors.initials: HR
authors.lastname: Jo
authors.affiliation: Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering, South Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, South Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering, South Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, South Korea. Electronic address: hyeonson@hanyang.ac.kr.
authors.forename: Hyeon
authors.initials: H
authors.lastname: Son
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C488171:carbamylated erythropoietin; D004921:Erythropoietin; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases
keywords: EPO; HDAC5; MEF2; cEPO