Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation Journal Article
| Authors: | Vorlova, S.; Rocco, G.; Lefave, C.; Jodelka, F.; Hess, K.; Hastings, M.; Henke, E.; Cartegni, L. |
| Article Title: | Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation |
| Abstract: | Alternative intronic polyadenylation (IPA) can generate truncated protein isoforms with significantly altered functions. Here, we describe 31 dominant-negative, secreted variant isoforms of receptor tyrosine kinases (RTKs) that are produced by activation of intronic poly(A) sites. We show that blocking U1-snRNP can activate IPA, indicating a larger role for U1-snRNP in RNA surveillance. Moreover, we report the development of an antisense-based method to effectively and specifically activate expression of individual soluble decoy RTKs (sdRTKs) to alter signaling, with potential therapeutic implications. In particular, a quantitative switch from signal transducing full-length vascular endothelial growth factor receptor-2 (VEGFR2/KDR) to a dominant-negative sKDR results in a strong antiangiogenic effect both on directly targeted cells and on naive cells exposed to conditioned media, suggesting a role for this approach in interfering with angiogenic paracrine and autocrine loops. © 2011 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; human cell; reverse transcription polymerase chain reaction; gene expression; culture medium; intron; enzyme activation; protein tyrosine kinase; vasculotropin receptor 2; angiogenesis; rna; tyrosine kinase receptor; autocrine effect; paracrine signaling; gene induction; small nuclear ribonucleoprotein; antiangiogenic activity; rna splicing; polyadenylation; antisense oligodeoxynucleotide; polyadenylic acid; tumor necrosis factor decoy receptor; intronic polyadenylation; umbilical vein endothelial cell |
| Journal Title: | Molecular Cell |
| Volume: | 43 |
| Issue: | 6 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2011-09-16 |
| Start Page: | 927 |
| End Page: | 939 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2011.08.009 |
| PROVIDER: | scopus |
| PUBMED: | 21925381 |
| PMCID: | PMC3781938 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: MOCEF" - "Source: Scopus" |
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