Activation of C-transactivation domain is essential for optimal HIF-1α-mediated transcriptional and angiogenic effects

被引:26
|
作者
Tal, Reshef [1 ,2 ,3 ]
Shaish, Aviv [1 ,2 ]
Bangio, Livnat [1 ]
Peled, Michael [1 ,2 ,3 ]
Breitbart, Eyal [1 ]
Harats, Dror [1 ,2 ]
机构
[1] Vasc Biogen Ltd, IL-60376 Or Yehuda, Israel
[2] Chaim Sheba Med Ctr, Inst Lipid & Atherosclerosis Res, IL-52621 Tel Hashomer, Israel
[3] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel
关键词
angiogenesis; endothelium; hypoxia; hypoxia-inducible factor 1;
D O I
10.1016/j.mvr.2008.03.002
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
HIF-1 is a transcription factor that regulates genes involved in oxygen homeostasis. In normoxia, degradation of the HIF-1 alpha subunit is enabled by two prolyl hydroxylations at residues P402 and P564, while inactivation occurs through asparaginyl hydroxylation at residue N803 within its C-transactivation domain (C-TAD). For therapeutic angiogenesis purposes, HIF-1 alpha stabilization was previously achieved by either deleting its oxygen-dependent degradation domains, or introducing two proline point mutations at residues P402 and P564. We assessed the hypothesis that constitutive activation of HIF-1 alpha in addition to its stabilization would result in greater HIF-1 alpha transcriptional activity and angiogenic effects than mere stabilization of the molecule. For this, we constructed a Triple mutant HIF-1 alpha (TM), bearing mutations P402A and P564G N803A. Transient co-transfections with hypoxia-responsive element-luciferase construct revealed 2 to 2.5-fold increase in transcriptional activity of TM compared with P402A P564G double mutant and wild-type HIF-1 alpha. In-vitro angiogenesis assay using transfected human umbilical vein enclothelial cells (HUVEC) showed that TM stimulated tube formation to a greater extent than both P402A P564G mutant and wild-type HIF-1a. Accordingly, ELISA revealed that VEGF levels within the transfected HUVEC were about 10-fold greater with the TM. Conclusions: Constitutive activation of the HIF-1 alpha C-TAD, and not merely stabilization of the HIF-1 alpha molecule, is essential for optimal HIF-mediated transcriptional and angiogenic effects. This finding could have important implications for therapeutic angiogenesis using HIF-1 alpha. (c) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:1 / 6
页数:6
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