WT1 mutants reveal SRPK1 to be a novel downstream angiogenesis target by altering VEGF splicing
Cancer Cell 20, 768-80 (2011) - PMID: 22172722
Authors: Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, Cheung MK, Ni L, Kase S, Rennel ES, Symonds KE, Nowak DG, Royer-Pokora B, Saleem MA, Hagiwara M, Schumacher VA, Harper SJ, Hinton DR, Bates DO, Ladomery MR.
Angiogenesis is regulated by the balance of proangiogenic VEGF and antiangiogenic VEGFb splice isoforms. Mutations in WT1, the Wilms’ tumor suppressor gene, suppress VEGFb and cause abnormal gonadogenesis, renal failure, and Wilms’ tumors. In WT1 mutant cells, reduced VEGFb 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.
Keywords: WT1,VEGF,SRPK1,alternative splicing,cancer,angiogenesis