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

Cancer Cell. 2011 Dec 13;20(6):768-80. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / metabolism
  • Choroidal Neovascularization / pathology
  • Denys-Drash Syndrome / genetics
  • Denys-Drash Syndrome / metabolism
  • Denys-Drash Syndrome / pathology
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Luciferases, Renilla / biosynthesis
  • Luciferases, Renilla / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / blood supply
  • Neovascularization, Pathologic / genetics*
  • Nuclear Proteins / metabolism
  • Podocytes / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA Splicing / genetics
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors
  • Vascular Endothelial Growth Factor B / genetics*
  • Vascular Endothelial Growth Factor B / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • WT1 Proteins / genetics*

Substances

  • Nuclear Proteins
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • RNA-Binding Proteins
  • VEGFB protein, human
  • Vascular Endothelial Growth Factor B
  • WT1 Proteins
  • Serine-Arginine Splicing Factors
  • Luciferases, Renilla
  • SRPK1 protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein-Serine-Threonine Kinases