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

被引：205

作者：

Amin, Elianna M. ^{[1
,2
]}

Oltean, Sebastian ^{[1
]}

Hua, Jing ^{[1
]}

Gammons, Melissa V. R. ^{[1
]}

Hamdollah-Zadeh, Maryam ^{[1
]}

Welsh, Gavin I. ^{[3
]}

Cheung, Man-Kim ^{[2
]}

Ni, Lan ^{[3
]}

Kase, Satoru ^{[4
]}

Renne, Emma S. ^{[1
]}

Symonds, Kirsty E. ^{[1
]}

Nowak, Dawid G. ^{[1
]}

Royer-Pokora, Brigitte ^{[5
]}

Saleem, Moin A. ^{[3
]}

Hagiwara, Masatoshi ^{[6
]}

Schumacher, Valerie A. ^{[5
,7
,8
]}

Harper, Steven J. ^{[1
]}

Hinton, David R. ^{[4
]}

Bates, David O. ^{[1
]}

Ladomery, Michael R. ^{[2
]}

机构：

[1] Univ Bristol, Microvasc Res Labs, Bristol Heart Inst, Sch Physiol & Pharmacol, Bristol BS2 8EJ, Avon, England

[2] Univ W England, Fac Hlth & Life Sci, Ctr Biomed Res, Bristol BS16 1QY, Avon, England

[3] Univ Bristol, Southmead Hosp, Acad & Childrens Renal Unit, Bristol BS10 5NB, Avon, England

[4] Univ So Calif, Dept Pathol, Keck Sch Med, Los Angeles, CA 90089 USA

[5] Univ Dusseldorf, Inst Human Genet & Anthropol, Fac Med, D-40225 Dusseldorf, Germany

[6] Kyoto Univ, Grad Sch Med, Dept Anat & Dev Biol, Kyoto 6068501, Japan

[7] Childrens Hosp Boston, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

来源：

CANCER CELL | 2011年 / 20卷 / 06期

基金：

英国惠康基金;

关键词：

ENDOTHELIAL GROWTH-FACTOR; WILMS-TUMOR; ANTIANGIOGENIC ISOFORMS; VEGF(165)B; VARIANT; GENE; NEOVASCULARIZATION; OVEREXPRESSION; SUPPRESSOR; RNA;

D O I：

10.1016/j.ccr.2011.10.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Angiogenesis is regulated by the balance of proangiogenic VEGF(165) and antiangiogenic VEGF165b 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.

引用

页码：768 / 780

页数：13

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