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

Elianna M. Amin et al., Cancer Cell 20, 768–780( 2011)

Speaker: (Zih-Cian Su) 蘇資茜                                            Time:5/23/2012, 1:00-2:00 PM

Commentator: Li-Wha Wu, Ph.D (吳梨華老師)                Location: Room 601

Abstract

WT1 is a zinc finger transcription factor that is expressed throughout urogenital development and continues to be expressed in mature podocytes. Denys-Drash Syndrome (DDS) is caused by WT1 mutation. According to the study of Schumcher et al. , the laser-dissected glomeruli from patients with DDS lack VEGF(Vascular endothelial growth factor)165b, which is a isoform of VEGF165.These two isoforms are generated by alternate splice-site selection in the terminal exon. Proximal splice-site selection (PSS) in exon 8 results in proangiogenic VEGF165 isoforms, whereas distal splice-site selection (DSS) results in antiangiogenic VEGF165b isoforms. As DDS-causing mutations in WT1 can alter VEGF splicing, authors have investigated this link between WT1 and splicing of the VEGF transcript. The alternative splicing of VEGF is determined by SR (serine-arginine-rich proteins), such as SRSF1, SRSF2 and SRSF6. SRSF1 favored PSS (to form VEGF165), whereas SRSF6 preferentially select DSS (to form VEGF165b). In this paper, they found that SRSF1 was localized predominantly in the nucleus of DDS cell. It is known that SRSF1 nuclear localization is brought about by phosphorylation by a number of splicing factors, including SRPK1(SR protein kinases 1). Authors demonstrated that mutant WT1 couldn’t bind to SRPK1 promoter, and the lacked WT1-mediated transcriptional repression led to the elevation of SRPK1 in human DDS. When SRPK1 wasupregulated and the SRSF1 is localized to nucleus, therefore, the VEGF transcripts were preferentially spliced to VEGF165 rather than VEGF165b. These findings explain why DDS patients have increased risk of highly vascularized tumors.

References

1. Schumacher., et al. Impaired glomerular maturation and lack of VEGF165b in Denys-Drashsyndrome. J. Am. Soc. Nephrol. 18, 719–729 (2007).