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Mol Cell. 2011 Sep 16;43(6):927-39. doi: 10.1016/j.molcel.2011.08.009.

Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation.

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1
Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.

PMID:
21925381
PMCID:
PMC3781938
DOI:
10.1016/j.molcel.2011.08.009
[Indexed for MEDLINE]
Free PMC Article
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