WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing

Amin, E., Oltean, S., Hua, J., Gammons, M., Hamdollah-Zadeh, M., Welsh, G., Cheung, M.-K., Ni, L., Kase, S., Rennel, E., Symonds, K., Nowak, D., Royer-Pokora, B., Saleem, M., Hagiwara, M., Schumacher, Valérie, Harper, S., Hinton, D., Bates, D. and Ladomery, M. (2011) WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell, 20 (6). pp. 768-780. ISSN 1535-6108

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Publisher's URL: http://dx.doi.org/10.1016/j.ccr.2011.10.016

Abstract

Angiogenesis is regulated by the balance of proangiogenic VEGF(165) and antiangiogenic VEGF(165)b splice isoforms. Mutations in WT1, the Wilms' tumor suppressor gene, suppress VEGF(165)b and cause abnormal gonadogenesis, renal failure, and Wilms' tumors. In WT1 mutant cells, reduced VEGF(165)b 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.

Item Type:Article
Uncontrolled Keywords:WT1, VEGF, SRPK1, alternative splicing, cancer, angiogenesis
ID Code:16366
Deposited By: Dr M. Ladomery
Deposited On:12 Jan 2012 11:04
Last Modified:07 Feb 2014 07:45

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