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

doi:10.1039/c0sc00297f

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 journal › Article (Academic Journal) › peer-review

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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 contribution	Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms
Original language	English
Pages (from-to)	273 - 278
Number of pages	5
Journal	Chemical Science
Volume	2
DOIs	https://doi.org/10.1039/c0sc00297f
Publication status	Published - 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

@article{7800e5642f504934965229bc05fa8f79,

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 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.",

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

year = "2010",

month = aug,

doi = "10.1039/c0sc00297f",

language = "English",

volume = "2",

pages = "273 -- 278",

journal = "Chemical Science",

issn = "2041-6539",

publisher = "Royal Society of Chemistry",

}

Woolard, J, Vousden, W, Moss, SJ, Krishnakumar, A, Gammons, MVR, Nowak, DG, Dixon, N, Micklefield, J, Spannhoff, A, Bedford, MT, Gregory, MA, Martin, CJ, Leadlay, PF, Zhang, MQ, Harper, SJ, Bates, DO & Wilkinson, B 2010, 'Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms', Chemical Science, vol. 2, pp. 273 - 278. https://doi.org/10.1039/c0sc00297f

TY - JOUR

T1 - Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms

AU - Woolard, J

AU - Vousden, W

AU - Moss, S J

AU - Krishnakumar, A

AU - Gammons, M V R

AU - Nowak, D G

AU - Dixon, N

AU - Micklefield, J

AU - Spannhoff, A

AU - Bedford, M T

AU - Gregory, M A

AU - Martin, C J

AU - Leadlay, P F

AU - Zhang, M Q

AU - Harper, S J

AU - Bates, DO

AU - Wilkinson, B

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

U2 - 10.1039/c0sc00297f

DO - 10.1039/c0sc00297f

M3 - Article (Academic Journal)

SN - 2041-6539

VL - 2

SP - 273

EP - 278

JO - Chemical Science

JF - Chemical Science

ER -

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

Abstract

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