GLUT1 glucose transporter gene transcription is repressed by Sp3.: Evidence for a regulatory role of Sp3 during myogenesis
GLUT1 glucose transporter gene transcription is repressed by Sp3.: Evidence for a regulatory role of Sp3 during myogenesis
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DOI：
10.1006/jmbi.1999.3216
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发表时间：
1999-11-19
影响因子：
5.6
通讯作者：
Zorzano, A
中科院分区：
文献类型：
--
作者：
Fandos, C;Sánchez-Feutrie, M;Zorzano, A
在胎儿时期，GLUT1葡萄糖转运蛋白在增殖和转化细胞以及组织中高度表达。然而，调节GLUT1基因表达的机制在很大程度上仍然未知。在这里，我们证明了Sp3蛋白与GLUT1近端启动子基因结合并抑制肌肉和非肌肉细胞的转录活性。在成肌细胞核提取物中检测到两种不同的Sp3翻译产物（110和74 kDa），这两种Sp3蛋白都抑制GLUT1基因的转录活性。Sp3对GLUT1基因转录活性的抑制作用大于刺激作用。此外，Sp3与GLUT1基因近端启动子结合的取消完全阻断了对Sp3的反应。我们提供的证据表明，Sp3蛋白的表达是受调节的：在肌肉细胞中，这可能是控制GLUT1。因此，在诱导igf - ii依赖性肌生成后，Sp3蛋白在早期Spl未发生变化的情况下上调。此外，MyoD的强迫过表达引起细胞Sp3/Sp1比值的增强，这伴随着GLUT1表达的降低。在肌肉形成后期，Sp3大量表达，而Spl明显下调。总之，我们提供的直接证据表明，转录因子Sp3抑制非肌肉细胞和肌肉细胞中的基因表达，这可能通过与GLUT1基因启动子结合在胎儿心脏中起作用。这是对GLUT1基因转录抑制因子的首次描述。此外，我们提出Sp3和sp1比值的变化调节GLUT1启动子活性，这对于与肌肉形成相关的GLUT1下调至关重要。(C) 1999学术出版社。
GLUT1 glucose transporters are highly expressed in proliferating and transformed cells as well as in tissues during fetal life. However, the mechanisms that regulate GLUT1 gene expression remain largely unknown. Here, we demonstrate that Sp3 proteins bind to the GLUT1 proximal promoter Gene and inhibit transcriptional activity in muscle and non-muscle cells. Two different Sp3 translational products (110 and 74 kDa) derived from differential translational initiation were detected in nuclear extracts from myoblast cells, and both Sp3 protein species inhibited GLUT1 gene transcriptional activity. The inhibitory effect of Sp3 was dominant over the stimulatory effect of Spl on transcriptional activity of GLUT1 gene. Furthermore, abolition of Sp3 binding to the proximal promoter of GLUT1 gene completely blocked the response to Sp3.We provide evidence that the expression of Sp3 protein is subject to regulation:in muscle cells and that this is likely to control GLUT1. Thus, Sp3 protein was up-regulated in the absence of changes in Spl early after the induction of IGF-II-dependent myogenesis. Furthermore, forced overexpression of MyoD caused an enhancement in the cellular Sp3/Sp1 ratio which was concomitant to a reduced GLUT1 expression. Later during myogenesis, Sp3 expression was substantial whereas Spl was markedly down-regulated.In summary, we provide direct evidence that the transcription factor Sp3 represses gene expression in non-muscle and muscle cells and this is likely to operate in fetal heart by binding to the GLUT1 gene promoter. This is the first description of a repressor of GLUT1 gene transcription. Furthermore, we propose that variations in the ratio of Sp3 versus Spl regulate GLUT1 promoter activity and this is crucial in the down-regulation of GLUT1 associated to myogenesis. (C) 1999 Academic Press.