Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression
Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression
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DOI：
10.1093/emboj/19.5.1034
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发表时间：
2000-03-01
期刊：
影响因子：
11.4
通讯作者：
Levens, D
中科院分区：
文献类型：
--
作者：
He, LS;Liu, JH;Levens, D
C-myc调控区包括一大组转录因子的结合位点，本研究表明，在缺乏与单链融合基因结合的FBP[远上游元件(FUSE)结合蛋白]的情况下，该集合的其余部分无法维持内源性c-myc的表达。通过复制缺陷型腺病毒载体表达的缺乏效应活性的显性负性FBP DNA结合域或反义FBP RNA可阻止细胞增殖，并抑制P1和P2启动子的天然c-myc转录。显性负性FBP最初增强了FUSE的单链特性：然而，一旦c-myc表达被取消，FUSE上的融化就不再被支持。相反，对于反义FBP RNA，随着内源c-myc转录的下降，融合蛋白的单链特性单调下降，因为转录是体内超螺旋的主要来源，我们认为FBP通过结合扭转应变的DNA来直接测量启动子的活性。我们还表明，FUSE被预测为一个扭转调节开关，准备调节c-myc，并对大量因子进行更高阶的调节。
The c-myc regulatory region includes binding sites for a large set of transcription factors, The present studies demonstrate that in the absence of FBP [far upstream element (FUSE)-binding protein], which binds to the single-stranded FUSE, the remainder of the set fails to sustain endogenous c-myc expression. A dominant-negative FBP DNA-binding domain lacking effector activity or an antisense FBP RNA, expressed via replication-defective adenovirus vectors, arrested cellular proliferation and extinguished native c-myc transcription from the P1 and P2 promoters. The dominant-negative FBP initially augmented the single-stranded character of FUSE: however once c-myc expression was abolished, melting at FUSE could no longer be supported. In contrast, with antisense FBP RNA, the single-stranded character of FUSE decreased monotonically as the transcription of endogenous c-myc declined, Because transcription is the major source of super-coiling in vivo, we propose that by binding torsionally strained DNA, FBP measures promoter activity directly. we also show that FUSE is predicted to behave as a torsion-regulated switch poised to regulate c-myc and to confer a higher order regulation on a large repertoire of factors.