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- Title
Regulation of soluble Flt-1 (VEGFR-1) production by hnRNP D and protein arginine methylation.
- Authors
Ikeda, Takayuki; Yoshitomi, Yasuo; Saito, Hidehito; Shimasaki, Takeo; Yamaya, Hideki; Kobata, Takashi; Ishigaki, Yasuhito; Tomosugi, Naohisa; Yoshitake, Yoshino; Yonekura, Hideto
- 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.
- Subjects
PROTEIN arginine methyltransferases; METHYLATION; NUCLEOPROTEINS; MICROVASCULAR angina; ENDOTHELIAL cells; GENETIC overexpression
- Publication
Molecular & Cellular Biochemistry, 2016, Vol 413, Issue 1/2, p155
- ISSN
0300-8177
- Publication type
Article
- DOI
10.1007/s11010-015-2649-y