MODULATION OF GENE-EXPRESSION BY CALRETICULIN BINDING TO THE GLUCOCORTICOID RECEPTOR
MODULATION OF GENE-EXPRESSION BY CALRETICULIN BINDING TO THE GLUCOCORTICOID RECEPTOR
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DOI：
10.1038/367476a0
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发表时间：
1994-02-03
期刊：
影响因子：
64.8
通讯作者：
MICHALAK, M
中科院分区：
文献类型：
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作者：
BURNS, K;DUGGAN, B;MICHALAK, M
钙网蛋白是一种多功能蛋白，在内质网的管腔中起主要的钙结合(储存)蛋白的作用。在核2中也发现了它，这表明它可能在转录调控中发挥作用。据报道，钙网蛋白与合成肽KLGFFKR3结合，KLGFFKR3与核受体4-6超家族DNA结合域中的氨基酸序列几乎相同。钙网蛋白能与这些受体的DNA结合域相互作用并影响它们的功能吗？在此，我们报道了钙网蛋白的氨基末端与糖皮质激素受体的DNA结合域相互作用，并阻止该受体与其特定的糖皮质激素反应元件结合。在小鼠L成纤维细胞中过表达钙网蛋白抑制糖皮质激素敏感报告基因和编码细胞色素P450的内源性糖皮质激素敏感基因的转录激活。综上所述，这些结果表明，钙网蛋白可能在基因转录中起重要作用，调节糖皮质激素受体，或许还调节核受体超家族的其他成员。
CALRETICULIN is a multifunctional protein that acts as a major Ca2+-binding (storage) protein in the lumen of the endoplasmic reticulum1. It is also found in the nucleus2, suggesting that it may have a role in transcription regulation. Calreticulin has been reported to bind to the synthetic peptide KLGFFKR3, which is almost identical to an amino-acid sequence in the DNA-binding domain of the superfamily of nuclear receptors4-6. Could calreticulin interact with the DNA-binding domain of these receptors and affect their function? Here we report that the amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Overexpression of calreticulin in mouse L fibroblasts inhibits glucocorticoid-response-mediated transcriptional activation of a glucocorticoid-sensitive reporter gene and of the endogenous, glucocorticoid-sensitive gene encoding cytochrome P450. Together these results indicate that calreticulin may be important in gene transcription, regulating the glucocorticoid receptor and perhaps other members of the superfamily of nuclear receptors.