title: AUF1-RGG peptides up-regulate the VEGF antagonist, soluble VEGF receptor-1 (sFlt-1).
abstract: The macrophage is essential to the innate immune response, but also contributes to human disease by aggravating inflammation. Under severe inflammation, macrophages and other immune cells over-produce immune mediators, including vascular endothelial growth factor (VEGF). The VEGF protein stimulates macrophage activation and induces macrophage migration. A natural inhibitor of VEGF, the soluble VEGF receptor (sFlt-1) is also produced by macrophages and sFlt-1 has been used clinically to block VEGF. In macrophages, we have shown that the mRNA regulatory protein AUF1/hnRNP D represses VEGF gene expression by inhibiting translation of AURE-regulated VEGF mRNA. Peptides (AUF1-RGG peptides) that are modeled on the arginine-glycine-glycine (RGG) motif in AUF1 also block VEGF expression. This report shows that the AUF1-RGG peptides reduce two other AURE-regulated genes, TNF and GLUT1. Three alternative splice variants of sFlt-1 contain AURE in their 3'UTR, and in an apparent paradox, AUF1-RGG peptides stimulate expression of these three sFlt-1 Variants. The AUF1-RGG peptides likely act by distinct mechanisms with complimentary effects to repress VEGF gene expression and over-express the endogenous VEGF blocking agent, sFlt-1. The AUF1-RGG peptides are novel reagents that reduce VEGF and other inflammatory mediators, and may be useful tools to suppress severe inflammation.
authors.affiliation: Veterans Administration Research Service, White River Junction, VT 05009, USA; Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Fellows
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Nichols
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002460:Cell Line; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D051272:Glucose Transporter Type 1; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: AU-rich element; AUF1; AUF1-RGG; AURE; GLUT1; RGG; Soluble VEGFR-1; TNF; UTR; VEGF; arginine-glycine-glycine; arginine-glycine-glycine region of AUF1; glucose transporter-1; hnRNP D; sFlt-1; soluble VEGF receptor-1 (sVEGFR-1); the AUF1/hnRNP-D mRNA binding protein; tumor necrosis factor-α; untranslated region of mRNA; vascular endothelial growth factor