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学科主题: Oncology
题名: U19/Eaf2 Binds to and Stabilizes von Hippel-Lindau Protein
作者: Xiao, Wuhan6; Ai, Junkui; Habermacher, Geoffrey4; Volpert, Olga4; Yang, Ximing3; Zhang, Ai-yuan; Hahn, Junghyun4; Cai, Xiaoyan4; Wang, Zhou1, 2, 4, 5
通讯作者: Wang, Z, Univ Pittsburgh, Coll Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA
关键词: TUMOR-SUPPRESSOR PROTEIN ; CELL-PROLIFERATION ; UBIQUITIN LIGASE ; RENAL-CARCINOMA ; VASCULAR TUMORS ; HIF-ALPHA ; VHL GENE ; COMPLEX ; CANCER ; INACTIVATION
刊名: CANCER RESEARCH
发表日期: 2009-03-15
DOI: 10.1158/0008-5472.CAN-08-2595
卷: 69, 期:6, 页:2599-2606
收录类别: SCI
文章类型: Article
部门归属: [Wang, Zhou] Univ Pittsburgh, Coll Med, Dept Urol, Pittsburgh, PA 15232 USA; [Wang, Zhou] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA; [Yang, Ximing] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA; [Habermacher, Geoffrey; Volpert, Olga; Hahn, Junghyun; Cai, Xiaoyan; Wang, Zhou] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA; [Wang, Zhou] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA; [Xiao, Wuhan] Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
资助者: NIH [R37 DK51193, R01 CA120386, P50 CA90386]; Mellam Family Foundation
类目[WOS]: Oncology
研究领域[WOS]: Oncology
摘要: Studies have firmly established a key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal spermatogenesis. Here, we report that knockout of the newly identified tumor suppressor U19/Eaf2 also caused vascular system abnormalities and aspermatogenesis, suggesting a potential link between U19/Eaf2 and pVHL. Coimmunoprecipitation and in vitro binding assays showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirement of the NH2 terminus of U19/Eaf2 and both the alpha and beta domains of pVHL for this binding. U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase studies. Testes and mouse embryonic fibroblasts (MEF) derived from U19/Eaf2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL indeed requires U19/Eaf2. As expected, U19/Eaf2 knockout MEF cells exhibited an increased level and activity of hypoxia-inducible factor 1 alpha (HIF1 alpha), a protein typically regulated via a pVHL-mediated degradation pathway. Furthermore, angiogenesis in a Matrigel plug assay was significantly increased in U19/Eaf2 knockout mice. The above observations argue that U19/Eaf2 can modulate HIF1 alpha and angiogenesis, possibly via direct binding and stabilization of pVHL. [Cancer Res 2009;69(6):2599-606]
英文摘要: Studies have firmly established a key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal spermatogenesis. Here, we report that knockout of the newly identified tumor suppressor U19/Eaf2 also caused vascular system abnormalities and aspermatogenesis, suggesting a potential link between U19/Eaf2 and pVHL. Coimmunoprecipitation and in vitro binding assays showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirement of the NH2 terminus of U19/Eaf2 and both the alpha and beta domains of pVHL for this binding. U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase studies. Testes and mouse embryonic fibroblasts (MEF) derived from U19/Eaf2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL indeed requires U19/Eaf2. As expected, U19/Eaf2 knockout MEF cells exhibited an increased level and activity of hypoxia-inducible factor 1 alpha (HIF1 alpha), a protein typically regulated via a pVHL-mediated degradation pathway. Furthermore, angiogenesis in a Matrigel plug assay was significantly increased in U19/Eaf2 knockout mice. The above observations argue that U19/Eaf2 can modulate HIF1 alpha and angiogenesis, possibly via direct binding and stabilization of pVHL. [Cancer Res 2009;69(6):2599-606]
关键词[WOS]: TUMOR-SUPPRESSOR PROTEIN ; CELL-PROLIFERATION ; UBIQUITIN LIGASE ; RENAL-CARCINOMA ; VASCULAR TUMORS ; HIF-ALPHA ; VHL GENE ; COMPLEX ; CANCER ; INACTIVATION
语种: 英语
WOS记录号: WOS:000264541300055
ISSN号: 0008-5472
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/152342/7810
Appears in Collections:中科院水生所知识产出(2009年前)_期刊论文

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作者单位: 1.Univ Pittsburgh, Coll Med, Dept Urol, Pittsburgh, PA 15232 USA
2.Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA
3.Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA
4.Northwestern Univ, Dept Urol, Chicago, IL 60611 USA
5.Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA
6.Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China

Recommended Citation:
Xiao, Wuhan; Ai, Junkui; Habermacher, Geoffrey; Volpert, Olga; Yang, Ximing; Zhang, Ai-yuan; Hahn, Junghyun; Cai, Xiaoyan; Wang, Zhou.U19/Eaf2 Binds to and Stabilizes von Hippel-Lindau Protein,CANCER RESEARCH,2009,69(6):2599-2606
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