FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β
FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β
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FHL 家族成员通过阻断 HIF1α 和 HIF1β 二聚化抑制血管内皮生长因子表达
DOI：
10.1002/iub.1089
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发表时间：
2012-11-01
期刊：
影响因子：
4.6
通讯作者：
Ye, Qinong
中科院分区：
文献类型：
--
作者：
Lin, Jing;Qin, Xi;Ye, Qinong
四个半LIM结构域（FHL）蛋白属于仅LIM蛋白家族，其已经涉及各种类型癌症的发展和进展。然而，FHL蛋白在肿瘤血管生成中的作用仍有待阐明。在此，我们证明FHL 1 -3降低血管内皮生长因子（VEGF）的启动子活性和表达，VEGF是肿瘤生长和进展中血管生成的关键调节因子，也是转录因子缺氧诱导因子1（HIF 1a/HIF 1 β）的重要靶基因。FHL 1 -3在体内外均与HIF 1a相互作用。FHL 1的单个LIM结构域足以与HIF 1a相互作用。FHL 1与含有碱性螺旋-环-螺旋（bHLH）基序和PER-ARNT-SIM结构域的HIF 1a区域相互作用，这两者都有助于与HIF 1 β和DNA结合的二聚化。FHL 1 -3抑制HIF 1的转录活性和HIF 1介导的VEGF表达，在缺氧非依赖性的方式。此外，FHL 1阻断HIF 1a-HIF 1 β异源二聚化和HIF 1a向VEGF启动子的募集。这些数据表明，FHL蛋白可能通过干扰HIF 1亚基的二聚化和DNA结合参与VEGF的负调控，并可能在肿瘤血管生成中发挥重要作用。(c)2012年IUBMB。IUBMB Life，64（11）：921930，2012
Four and a half LIM domain (FHL) proteins belong to a family of LIM-only proteins that have been implicated in the development and progression of various types of cancers. However, the role of FHL proteins in tumor angiogenesis remains to be elucidated. Herein, we demonstrate that FHL1-3 decrease the promoter activity and expression of vascular endothelial growth factor (VEGF), the key regulator of angiogenesis in cancer growth and progression as well as an important target gene of the transcription factor hypoxia-inducible factor 1 (HIF1a/HIF1 beta). FHL1-3 interacted with HIF1a both in vitro and in vivo. A single LIM domain of FHL1 was sufficient for its interaction with HIF1a. FHL1 interacted with the HIF1a region containing basic helix-loop-helix (bHLH) motif and PER-ARNT-SIM domain, both of which aid in dimerization with HIF1 beta and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1a-HIF1 beta heterodimerization and HIF1a recruitment to the VEGF promoter. These data suggest that FHL proteins are involved in negative regulation of VEGF possibly by interfering with the dimerization and DNA binding of HIF1 subunits and may play an important role in tumor angiogenesis. (c) 2012 IUBMB. IUBMB Life, 64(11): 921930, 2012