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 contribution
|Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms
|273 - 278
|Number of pages
|Published - Aug 2010