HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes
HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes
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DOI：
10.1016/j.bbrc.2006.05.177
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发表时间：
2006-08-04
影响因子：
3.1
通讯作者：
Hughes, Christopher C. W.
中科院分区：
文献类型：
--
作者：
Holderfield, Matthew T.;Henderson Anderson, April M.;Hughes, Christopher C. W.
bHLH转录因子HESR 1（CHF 2）在notch下游起作用，至少部分通过下调VEGF受体VEGFR 2来调节心血管发育和血管生成。令人惊讶的是，我们发现HESR 1与内皮细胞（EC）中的启动子相互作用不是通过直接结合到E盒，而是通过与GC盒结合蛋白的中间相互作用。HESR I的bHLH和橙子结构域足以在EC中抑制，可能是通过募集共抑制物，然而，不需要C末端YRPW基序。VEGFR 2启动子含有功能性起始元件但不含TATA盒，然而，TATA序列的添加使得启动子对HESR 1的抑制具有抗性。与这一发现一致，具有TATA盒的NrCAM、TK和CMV启动子不能被抑制。因此，HESR 1通过与SP-1样因子的相互作用抑制VEGFR 2，并且在TATA盒不存在的情况下需要Inr元件。我们的研究结果阐明了Notch/HESR 1调节VEGF诱导的血管生成的重要机制。(c)2006年爱思唯尔公司All rights reserved.
The bHLH transcription factor HESR1 (CHF2) acts downstream of notch to regulate cardiovascular development and angiogenesis, at least in part through down-regulation of the VEGF receptor, VEGFR2. Surprisingly, we find that HESR1 interacts with the promoter in endothelial cells (EC) not through direct binding to the E-boxes, but through intermediary interactions with GC-box-binding proteins. The bHLH and orange domains of HESR I are sufficient for repression in EC, likely through recruitment of co-repressors, however, the C-terminal YRPW motif is not required. The VEGFR2 promoter contains a functional initiator element but no TATA box, however, addition of a TATA sequence renders the promoter resistant to inhibition by HESR1. In agreement with this finding, the NrCAM, TK, and CMV promoters, which have TATA boxes, cannot be repressed. Thus, HESR1 represses VEGFR2 through interactions with SP-1-like factors and requires an Inr element in the absence of a TATA box. Our findings illuminate an important mechanism for notch/ HESR1 regulation of VEGF-induced angiogenesis. (c) 2006 Elsevier Inc. All rights reserved.