WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.
WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.
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DOI：
10.1016/j.ccr.2011.10.016
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发表时间：
2011-12-13
期刊：
影响因子：
50.3
通讯作者：
Ladomery MR
中科院分区：
文献类型：
--
作者：
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
血管生成受促血管生成VEGF165和抗血管生成VEGF165b剪接异构体的平衡调节。Wilms肿瘤抑制基因WT1的突变抑制VEGF165b，导致性腺激素异常、肾功能衰竭和Wilms肿瘤。在WT1突变细胞中，VEGF165b的减少是由于缺乏WT1介导的剪接因子激酶SRPK1的转录抑制。WT1与SRPK1启动子结合，通过特定的WT1结合位点抑制SRPK1的表达。在WT1突变细胞中，srpk1介导的致癌RNA结合蛋白SRSF1的过度磷酸化调节了VEGF的剪接，并使WT1突变细胞促血管生成。野生型WT1、SRSF1或SRPK1的敲低和SRPK1的抑制可以逆转VEGF剪接的改变，从而阻止体外和体内血管生成以及相关的肿瘤生长。
Angiogenesis is regulated by the balance of pro-angiogenic VEGF165 and anti-angiogenic VEGF165b splice isoforms. Mutations in WT1, the Wilms’ tumour suppressor gene, suppress VEGF165b and cause abnormal gonadogenesis, renal failure and Wilms’ tumours. 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 pro-angiogenic. Altered VEGF splicing was reversed by wildtype WT1, knockdown of SRSF1 or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumour growth.
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