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Selective down‐regulation of anti‐angiogenic splice variants of VEGF by IGF‐1 is mediated by PKC, PI‐3K and SRPK1/2
Author(s) -
Nowak Dawid G,
Woolard Jeanette,
Ladomery Michael,
Harper Steve J,
Bates Dave O
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.603.8
Subject(s) - alternative splicing , kinase , gene isoform , rna splicing , exon , angiogenesis , phosphorylation , protein kinase c , sr protein , vascular endothelial growth factor , microbiology and biotechnology , chemistry , biology , cancer research , vegf receptors , biochemistry , gene , rna
VEGF, the predominant regulatory molecule in angiogenesis, is differentially spliced in its terminal exon (exon 8) to produce either pro‐angiogenic VEGF xxx or anti‐angiogenic VEGF xxx b isoforms. We have shown that IGF‐1 specifically down‐regulates VEGF xxx b expression in proliferating podocytes. Here, we investigated the role of PKC and PI‐3K in IGF‐1‐dependent down‐regulation of VEGF xxx b expression after 48 hours of treatment. VEGF xxx b proteins were measured in cell lysates by isoform‐specific ELISA. VEGF xxx b expression was decreased by IGF‐1 (0.28±0.05 fold to control). BIMI, an inhibitor of PKC kinases, prevented IGF‐1 down‐regulation of VEGF xxx b expression (1.14±0.04 fold to control). SRPIN340, an inhibitor of SRPK1/2 (serine‐arginine (SR) Protein Kinase 1 and 2) kinases implicated in splicing control by phosphorylating splicing factors, inhibited IGF‐1 down‐regulation of VEGF xxx b expression (1.17±0.14 fold). These results indicate that IGF‐1 decreases the synthesis of VEGF xxx b isoforms in proliferating podocytes through PKC, PI‐3K and SRPK1/2 kinases. Funded by the BHF (FS04/09, and BS06/005).