title: Regulation of soluble Flt-1 (VEGFR-1) production by hnRNP D and protein arginine methylation.
abstract: Soluble fms-like tyrosine kinase-1 (sFlt-1) functions as a potent inhibitor of angiogenesis by trapping vascular endothelial growth factor (VEGF). However, the precise regulatory mechanism of sFlt-1 production is unknown. Here, we report that vascular sFlt-1 production is regulated by heterogeneous nuclear ribonucleoprotein D (hnRNP D) and arginine methylation. We showed that hnRNP D bound to Flt-1 pre-mRNA and that hnRNP D overexpression decreased sFlt-1 mRNA in human microvascular endothelial cells (HMVECs). In contrast, the reduction of hnRNP D levels induced an increase in sFlt-1 production. Overexpression of an hnRNP D mutant in which the arginine residue of the known arginine methylation motif (arginine-glycine-glycine; RGG) was replaced with alanine did not reduce the level of soluble-form RNA produced from the Flt-1 minigene. Moreover, we demonstrated that overexpression of arginine methyltransferase decreased the soluble-form RNA level, whereas overexpression of arginine demethylase and addition of methyltransferase inhibitors increased sFlt-1 mRNA levels. These findings indicate that hnRNP D and arginine methylation play important roles in the regulation of Flt-1 mRNA alternative polyadenylation.
authors.affiliation: Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshitomi
authors.affiliation: Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Saito
authors.affiliation: Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Shimasaki
authors.affiliation: Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaya
authors.affiliation: Department of Cardiovascular Surgery, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobata
authors.affiliation: Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tomosugi
authors.affiliation: Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Yoshitake
authors.affiliation: Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan. yonekura@kanazawa-med.ac.jp.
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
mesh_terms: D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D055806:Microvessels / Q000166:cytology; D026723:Polyadenylation; D012333:RNA, Messenger / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D012333:RNA, Messenger; D001120:Arginine; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Alternative polyadenylation; Arginine methylation; VEGF; hnRNP D; sFlt-1