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WT1 Mutants Reveal SRPK1 to Be a Downstream Angiogenesis Target by Altering VEGF Splicing

Amin, Elianna M.; Gammons, Melissa V.R.; Welsh, Gavin I.; Rennel, Emma S.; Symonds, Kirsty E.; Nowak, Dawid G.; Saleem, Moin A.; Schumacher, Val�rie A.; Harper, Steven J.; Hinton, David R.; Bates, David O.; Oltean, Sebastian; Hua, Jing; Hamdollah-Zadeh, Maryam; Cheung, Man Kim; Ni, Lan; Ladomery, Michael; Kase, Satoru; Royer-Pokora, Brigitte; Hagiwara, Masatoshi

Authors

Elianna M. Amin

Melissa V.R. Gammons

Gavin I. Welsh

Emma S. Rennel

Kirsty E. Symonds

Dawid G. Nowak

Moin A. Saleem

Val�rie A. Schumacher

Steven J. Harper

David R. Hinton

David O. Bates

Sebastian Oltean

Jing Hua

Maryam Hamdollah-Zadeh

Man Kim Cheung

Lan Ni

Satoru Kase

Brigitte Royer-Pokora

Masatoshi Hagiwara



Abstract

Angiogenesis is regulated by the balance of proangiogenic VEGF 165 and antiangiogenic VEGF 165b splice isoforms. Mutations in WT1, the Wilms' tumor suppressor gene, suppress VEGF 165b and cause abnormal gonadogenesis, renal failure, and Wilms' tumors. In WT1 mutant cells, reduced VEGF 165b was due to lack of WT1-mediated transcriptional repression of the splicing-factor kinase SRPK1. WT1 bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding site. In WT1 mutant cells SRPK1-mediated hyperphosphorylation of the oncogenic RNA binding protein SRSF1 regulated splicing of VEGF and rendered WT1 mutant cells proangiogenic. Altered VEGF splicing was reversed by wild-type WT1, knockdown of SRSF1, or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumor growth. © 2011 Elsevier Inc.

Citation

Bates, D. O., Hinton, D. R., Harper, S. J., Schumacher, V. A., Saleem, M. A., Nowak, D. G., …Ladomery, M. (2011). WT1 Mutants Reveal SRPK1 to Be a Downstream Angiogenesis Target by Altering VEGF Splicing. Cancer Cell, 20(6), 768-780. https://doi.org/10.1016/j.ccr.2011.10.016

Journal Article Type Article
Publication Date Dec 13, 2011
Deposit Date Jan 12, 2012
Journal Cancer Cell
Print ISSN 1535-6108
Electronic ISSN 1878-3686
Publisher Elsevier (Cell Press)
Peer Reviewed Peer Reviewed
Volume 20
Issue 6
Pages 768-780
DOI https://doi.org/10.1016/j.ccr.2011.10.016
Keywords WT1, VEGF, SRPK1, alternative splicing, cancer, angiogenesis
Public URL https://uwe-repository.worktribe.com/output/956808
Publisher URL http://dx.doi.org/10.1016/j.ccr.2011.10.016