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Cancer Cell. 2011 Dec 13;20(6):768-80. doi: 10.1016/j.ccr.2011.10.016.

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

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1
Centre for Research in Biomedicine, University of the West of England, Bristol, UK.

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.

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PMID:
22172722
PMCID:
PMC3574979
DOI:
10.1016/j.ccr.2011.10.016
[Indexed for MEDLINE]
Free PMC Article

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