title: EPO gene expression promotes proliferation, migration and invasion via the p38MAPK/AP-1/MMP-9 pathway by p21WAF1 expression in vascular smooth muscle cells.
abstract: The use of recombinant human erythropoietin (rHuEpo) can lead to hypertrophy and hyperplasia, and has induced the proliferation of vascular smooth muscle cells (VSMCs). The effect of the EPO gene in the migration and invasion of VSMCs remains unclear. In this study, overexpression of the EPO gene increased the DNA synthesis and phosphorylation of ERK1/2 and p38MAPK in VSMCs. In addition, EPO gene expression induced the migration and invasion of VSMCs via the expression of MMP-9 by the activation of NF-κB and AP-1 binding. A blockade of p38MAPK by specific p38MAPK inhibitor SB203580 led to a suppression of the increased DNA synthesis, migration, and invasion of VSMCs that was induced by the EPO gene. SB203580 treatment blocked the increased expression of MMP-9 through the binding activity of AP-1. Transfection of the EPO gene with VSMCs was associated with the up-regulation of cyclin D1/CDK4, cyclin E/CDK2, and p21WAF1, and with the down-regulation of p27KIP1. The specific suppression of p21WAF1 expression by siRNA rescued the enhancement of DNA synthesis via the phosphorylation of p38MAPK and the increase in migration and invasion through AP-1-mediated MMP-9 expression in EPO gene transfectants. These novel findings demonstrate that p21WAF1 regulates the proliferation, migration and invasion of VSMC induced by EPO gene.
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Ansung 456-756, Republic of Korea.
authors.forename: Sung Lyea
authors.initials: SL
authors.lastname: Park
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Ansung 456-756, Republic of Korea.
authors.forename: Se Yeon
authors.initials: SY
authors.lastname: Won
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Ansung 456-756, Republic of Korea.
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Song
authors.affiliation: Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
authors.affiliation: Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nagao
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Ansung 456-756, Republic of Korea. Electronic address: sumoon66@dreamwiz.com.
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D016328:NF-kappa B; D015513:Oncogene Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D004921:Erythropoietin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580
keywords: AP-1; EPO gene; Migration; Vascular smooth muscle cells; p21WAF1; p38MAPK