Author/Authors :
Amin، نويسنده , , Elianna M. and Oltean، نويسنده , , Sebastian and Hua، نويسنده , , Jing and Gammons، نويسنده , , Melissa V.R. and Hamdollah-Zadeh، نويسنده , , Maryam and Welsh، نويسنده , , Gavin I. and Cheung، نويسنده , , Man-Kim and Ni، نويسنده , , Lan and Kase، نويسنده , , Satoru and Rennel، نويسنده , , Emma S. and Symonds، نويسنده , , Kirsty E. and Nowak، نويسنده , , Dawid G. and Royer-Pokora، نويسنده , , Brigitte and Saleem، نويسنده , , Moin A. and Hagiwara، نويسنده , , Masatoshi and Schumacher، نويسنده , , Valérie A. and Harper، نويسنده , , Steven J. and Hinton، نويسنده , , David R. and Bates، نويسنده , , David O. and Ladomery، نويسنده , , Michael R.، نويسنده ,
Abstract :
Summary
enesis is regulated by the balance of proangiogenic VEGF165 and antiangiogenic VEGF165b splice isoforms. Mutations in WT1, the Wilmsʹ tumor suppressor gene, suppress VEGF165b and cause abnormal gonadogenesis, renal failure, and Wilmsʹ tumors. In WT1 mutant cells, reduced VEGF165b 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.
