title: Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300.
abstract: Both erythropoietin (EPO) and carbamylated EPO (cEPO) have been shown to increase the length of neurites and spine density in neurons. However, the molecular mechanism underlying the EPO- and cEPO-induced neuronal differentiation has yet to be investigated. To address this issue, we investigated epigenetic modifications that regulate gene expression in neurons. Neurons treated with EPO or cEPO display an upregulation of E1A-binding protein (p300) and p300-mediated p53 acetylation, possibly increasing the transactivation activity of p53 on growth-associated protein 43 (GAP43). Treatment of cells with cEPO markedly increases spine formation and potentiates p300-mediated transactivation of PSD95, Shank2 and 3 compared to EPO. These results demonstrate that cEPO controls neuronal differentiation via acetylation of transcription factors and subsequent transactivation of target genes. These findings have important medical implications because cEPO is of interest in the development of therapeutic agents against neuropsychiatric disorders.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Miyeon
authors.initials: M
authors.lastname: Choi
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Ko
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: In Young
authors.initials: IY
authors.lastname: Lee
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Wang
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, College of Medicine and Institute of Mental Health, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Oh
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea. Electronic address: hyeonson@hanyang.ac.kr.
authors.forename: Hyeon
authors.initials: H
authors.lastname: Son
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C485686:Shank2 protein, rat; C120532:Shank3 protein, rat; C494088:Stat3 protein, rat; D016159:Tumor Suppressor Protein p53; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D051057:Proto-Oncogene Proteins c-akt
keywords: Hippocampus; Spine density; cEPO