title: Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms.
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 tumor 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 recombinant WW domains 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.
authors: Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, School of Veterinary Sciences, University of Bristol, Southwell Street Bristol, BS2 8EJ, UK. ; Tel: +44 (0)117 9289818;  dave.bates@bristol.ac.uk.
authors: Jeanette
authors: J
authors: Woolard
authors: William
authors: W
authors: Vousden
authors: Steven J
authors: SJ
authors: Moss
authors: Arjun
authors: A
authors: Krishnakumar
authors: Melissa Vr
authors: MV
authors: Gammons
authors: David G
authors: DG
authors: Nowak
authors: Neil
authors: N
authors: Dixon
authors: Jason
authors: J
authors: Micklefield
authors: Astrid
authors: A
authors: Spannhoff
authors: Mark T
authors: MT
authors: Bedford
authors: Matthew A
authors: MA
authors: Gregory
authors: Christine J
authors: CJ
authors: Martin
authors: Peter F
authors: PF
authors: Leadlay
authors: Ming Q
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authors: Zhang
authors: Steven J
authors: SJ
authors: Harper
authors: David O
authors: DO
authors: Bates
authors: Barrie
authors: B
authors: Wilkinson