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

EM Amin, S Oltean, J Hua, MV Gammons, AM Hamdollah-Zadeh, G Welsh, MK Cheung, L Ni, S Kase, ES Rennel, KE Symonds, DG Nowak, B Royer-Pokora, MA Saleem, M Hagiwara, VA Schumacher, SJ Harper, DR Hinton, DO Bates, MR Ladomery

Research output: Contribution to journalArticle (Academic Journal)peer-review

153 Citations (Scopus)

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.
Translated title of the contributionWT1 Mutants Reveal SRPK1 to Be a Downstream Angiogenesis Target by Altering VEGF Splicing
Original languageEnglish
Pages (from-to)768 - 780
Number of pages5
JournalCancer Cell
Volume20
Issue number6
DOIs
Publication statusPublished - Dec 2011

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