Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms

J Woolard, W Vousden, S J Moss, A Krishnakumar, M V R Gammons, D G Nowak, N Dixon, J Micklefield, A Spannhoff, M T Bedford, M A Gregory, C J Martin, P F Leadlay, M Q Zhang, S J Harper, DO Bates, B Wilkinson

Research output: Contribution to journalArticle (Academic Journal)

20 Citations (Scopus)

Abstract

The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning of a phage display library of colon tumour cell cDNAs identified the tandem WW domains of spliceosome-associated protein formin binding protein 21 (FBP21) as a novel molecular target of borrelidin, suggesting that borrelidin may act as a modulator of alternative splicing. In support of this idea, 1, and its more selective analog 2, bound to purified recombinantWWdomains of FBP21. They also altered the ratio of vascular endothelial growth factor (VEGF) isoforms in retinal pigmented endothelial (RPE) cells in favour of anti-angiogenic isoforms. Transfection of RPE cells with FBP21 altered the ratio in favour of pro-angiogenic VEGF isoforms, an effect inhibited by 2. These data implicate FBP21 in the regulation of alternative splicing and suggest the potential of borrelidin analogs as tools to deconvolute key steps of spliceosome function.
Translated title of the contributionBorrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms
Original languageEnglish
Pages (from-to)273 - 278
Number of pages5
JournalChemical Science
Volume2
DOIs
Publication statusPublished - Aug 2010

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    Woolard, J., Vousden, W., Moss, S. J., Krishnakumar, A., Gammons, M. V. R., Nowak, D. G., Dixon, N., Micklefield, J., Spannhoff, A., Bedford, M. T., Gregory, M. A., Martin, C. J., Leadlay, P. F., Zhang, M. Q., Harper, S. J., Bates, DO., & Wilkinson, B. (2010). Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms. Chemical Science, 2, 273 - 278. https://doi.org/10.1039/c0sc00297f