Beta-catenin inversely regulates vascular endothelial growth factor-D mRNA stability.
The angiogenic and lymphangiogenic vascular endothelial growth factor (VEGF)-D is the only member of the VEGF family that is not induced by hypoxia or by serum factors, but its induction is mediated by direct cell-cell contact. Here we show that VEGF-D mRNA is down-modulated either by beta-catenin mobilization from the cell membrane, by activation of the Wnt signaling pathway, or by transfection with the beta-catenin stable mutant. Down-modulation of beta-catenin by means of RNA interference showed an increase of VEGF-D mRNA steady state in fibroblasts. The beta-catenin-dependent decrease of VEGF-D mRNA is indirect and mainly due to reduced VEGF-D mRNA stability, as demonstrated by experiments of mRNA decay in the presence of transcription or translation inhibitors. By transient transfection of chimeric constructs carrying fusion of VEGF-D sequences under the control of the cytomegalovirus early promoter, we demonstrated that beta-catenin negative regulation is on the VEGF-D mRNA 3'-untranslated region. We mapped the VEGF-D mRNA-destabilizing element to a sequence, conserved between mouse and human VEGF-D, which contains an AU-rich element of group I. These results unveiled a new regulatory pathway for VEGF-D, which explains, at least in part, VEGF-D regulation in tumor progression.
Orlandini
Maurizio
M
Dipartimento di Biologia Molecolare, Università degli Studi di Siena, via Fiorentina 1-53100 Siena, Italy.
Semboloni
Serena
S
Oliviero
Salvatore
S
D020413:3' Untranslated Regions; D000818:Animals; D041702:BALB 3T3 Cells; D020029:Base Pairing; D001483:Base Sequence; D002118:Calcium / Q000032:analysis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D003470:Culture Media; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004355:Drug Stability; D004533:Egtazic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D020413:3' Untranslated Regions; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003470:Culture Media; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D042643:Vascular Endothelial Growth Factor D; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D004533:Egtazic Acid; D008156:Luciferases; D002118:Calcium