Regulation of Vascular Endothelial Growth Factor (VEGF) Splicing from Pro-angiogenic to Anti-angiogenic Isoforms

Autor: Coralie Hoareau-Aveilla, Elianna M. Amin, Michael Ladomery, Emma S. Rennel, Masatoshi Hagiwara, Steven J. Harper, Jeanette Woolard, David O. Bates, Dawid G. Nowak, Melissa V. Gammons, Gopinath Damodoran
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Vascular Endothelial Growth Factor A
ASF/SF2
Angiogenesis
SRPK1
RNA-binding protein
Angiogenesis Inhibitors
Biology
Protein Serine-Threonine Kinases
Retinal Neovascularization
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
SR protein
Growth Factors
Animals
Humans
Protein Isoforms
splice
RNA
Messenger
Enzyme Inhibitors
Insulin-Like Growth Factor I
Molecular Biology
030304 developmental biology
Cell Line
Transformed
0303 health sciences
Serine-Arginine Splicing Factors
Alternative splicing
Nuclear Proteins
RNA-Binding Proteins
Cell Biology
Molecular biology
VEGF
Cell biology
Vascular endothelial growth factor
Vascular endothelial growth factor A
Alternative Splicing
Disease Models
Animal
chemistry
030220 oncology & carcinogenesis
RNA/Splicing
RNA
Zdroj: The Journal of Biological Chemistry
ISSN: 1083-351X
0021-9258
Popis: Vascular endothelial growth factor (VEGF) is produced either as a pro-angiogenic or anti-angiogenic protein depending upon splice site choice in the terminal, eighth exon. Proximal splice site selection (PSS) in exon 8 generates pro-angiogenic isoforms such as VEGF(165), and distal splice site selection (DSS) results in anti-angiogenic isoforms such as VEGF(165)b. Cellular decisions on splice site selection depend upon the activity of RNA-binding splice factors, such as ASF/SF2, which have previously been shown to regulate VEGF splice site choice. To determine the mechanism by which the pro-angiogenic splice site choice is mediated, we investigated the effect of inhibition of ASF/SF2 phosphorylation by SR protein kinases (SRPK1/2) on splice site choice in epithelial cells and in in vivo angiogenesis models. Epithelial cells treated with insulin-like growth factor-1 (IGF-1) increased PSS and produced more VEGF(165) and less VEGF(165)b. This down-regulation of DSS and increased PSS was blocked by protein kinase C inhibition and SRPK1/2 inhibition. IGF-1 treatment resulted in nuclear localization of ASF/SF2, which was blocked by SPRK1/2 inhibition. Pull-down assay and RNA immunoprecipitation using VEGF mRNA sequences identified an 11-nucleotide sequence required for ASF/SF2 binding. Injection of an SRPK1/2 inhibitor reduced angiogenesis in a mouse model of retinal neovascularization, suggesting that regulation of alternative splicing could be a potential therapeutic strategy in angiogenic pathologies.
Databáze: OpenAIRE
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