Regulation of adrenomedullin gene transcription and degradation by the c-myc gene
Regulation of adrenomedullin gene transcription and degradation by the c-myc gene
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DOI：
10.1210/en.2003-0402
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Ozawa, N;Shichiri, M;Hirata, Y
肾上腺髓质素是一种最初从嗜铬细胞瘤中分离出来的血管扩张肽，已知可调节细胞的生长、凋亡和迁移。C-myc癌基因的过表达已被证明通过启动子元件抑制小鼠肾上腺髓质素基因。我们研究了c-myc是否调控大鼠和人肾上腺髓质素基因，因为它们的启动子区域似乎没有启动子元件。使用含有上游序列的荧光素酶报告结构证明了c-myc反式激活人肾上腺髓质素基因。使用一组通过靶向同源重组获得的c-myc表达差异的同源大鼠成纤维细胞系，我们发现在稳定高表达c-myc的细胞中肾上腺髓质素转录水平显著升高，而在两个含有c-myc纯合子缺失的独立细胞系中，肾上腺髓质素转录水平几乎没有下降。C-myc转基因促进了肾上腺髓质素mRNA的降解，导致细胞分泌的肾上腺髓质素样免疫反应性相对增加。这些结果表明，c-myc反式激活大鼠和人肾上腺髓质素基因，并加速肾上腺髓质素基因的降解。然而，c-myc不是肾上腺髓质素基因基础表达所必需的。
Adrenomedullin, a vasodilatory peptide originally isolated from pheochromocytoma, is known to regulate cell growth, apoptosis, and migration. Overexpression of the c-myc oncogene has been shown to suppress the mouse adrenomedullin gene via the initiator element. We investigated whether c-myc regulates rat and human adrenomedullin genes because there appears to be no initiator elements in their promoter regions. Transactivation of the human adrenomedullin gene by c-myc was demonstrated using a luciferase reporter construct containing an upstream sequence. Using a panel of isogenic rat fibroblast cell lines with differential c-myc expression obtained by targeted homologous recombination, we found markedly elevated adrenomedullin transcript levels in cells stably overexpressing c-myc but a minimal decrease in two independent cell lines containing a homozygous null deletion of c-myc. Degradation of adrenomedullin mRNA was enhanced by a c-myc transgene, resulting in a relatively reserved increase in cellular secretion of adrenomedullin-like immunoreactivity. These results indicate that c-myc transactivates rat and human adrenomedullin genes and accelerates the degradation rate of adrenomedullin mRNA. However, c-myc is not essential for basal expression of the adrenomedullin gene.