DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter
DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter
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DOI：
10.1074/jbc.m300596200
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发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Yan, BF
中科院分区：
文献类型：
--
作者：
Li, YX;Xie, MX;Yan, BF
人DEC(在软骨细胞中差异表达)、小鼠StrA(维甲酸刺激)和大鼠Sharp(分裂和毛发相关蛋白)构成了一类新的、在结构上不同的基本螺旋-环-螺旋蛋白。在每个物种中，鉴定出两个成员，它们在基本螺旋-环-螺旋区域的序列同源性分别为90%，在总蛋白质中的同源性接近40%。最近，我们报道了DEC1在结肠癌组织中大量表达，而在癌旁正常组织中不表达。本研究旨在扩展DEC1的表达研究，并确定DEC1和DEC2在结肠癌、肺和肾脏的癌-正常组织中是否具有相似的表达模式。无一例外，DEC1在癌中显著升高，而DEC2则相反。在稳定的转染体中，四环素诱导DEC1的表达导致DEC2的表达成比例下降。与DEC1共转染可抑制DEC2启动子报告基因的活性高达90%。在野生型DEC1中观察到了这种抑制，但没有观察到它的DNA结合缺陷突变体。对缺失和定点突变的研究发现，在近端的启动子中，E-box基序支持DEC1介导的抑制。这个电子信箱的中断明显地使记者无法对DEC1做出回应。我们的发现为DEC1指定了第一个通过直接DNA结合调节的靶基因。DEC/StrA/Sharp蛋白在DNA结合区高度相同，但在其他区域更加多样化。DEC1介导的对DEC2表达的抑制提供了一个重要的机制，即这些转录因子不仅通过调节其靶基因的表达，还通过调节同一类成员的表达来调节细胞功能。
Human DEC (differentially expressed in chondrocytes), mouse STRA (stimulated with retinoic acid), and rat SHARP (split and hairy related protein) proteins constitute a new and structurally distinct class of the basic helix-loop-helix proteins. In each species, two members are identified with a sequence identity of >90% in the basic helix-loop-helix region and similar to40% in the total proteins, respectively. Recently, we have reported that DEC1 is abundantly expressed in colon carcinomas but not in the adjacent normal tissues. The present study was undertaken to extend the expression study of DEC1 and to determine whether DEC1 and DEC2 had similar expression patterns among paired cancer-normal tissues from the colon, lung, and kidney. Without exceptions, DEC1 was markedly higher in the carcinomas, whereas the opposite was true with DEC2. In stable transfectants, tetracycline-induced expression of DEC1 caused proportional decreases in the expression of DEC2. Co-transfection with DEC1 repressed the activity of a DEC2 promoter reporter by as much as 90%. The repression was observed with wild type DEC1 but not its DNA binding-defective mutants. Studies with deletion and site-directed mutants located, in the proximal promoter, an E-box motif that supported the DEC1-mediated repression. Disruption of this E-box markedly abolished the ability of the reporter to respond to DEC1. Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding. DEC/STRA/SHARP proteins are highly identical in the DNA binding domain but much more diverse in other areas. DEC1-mediated repression on the expression of DEC2 provides an important mechanism that these transcription factors regulate the cellular function not only by modulating the expression of their target genes but also the expression of members within the same class.