AUF1 ls expressed in the developing brain, binds to AT-rich double-stranded DNA, and regulates enkephalin gene expression
AUF1 ls expressed in the developing brain, binds to AT-rich double-stranded DNA, and regulates enkephalin gene expression
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DOI：
10.1074/jbc.m511858200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Agoston, Denes V.
中科院分区：
文献类型：
--
作者：
Dobi, Albert;Szemes, Marianna;Agoston, Denes V.
在我们寻找控制脑啡肽（ENK）基因发育调节表达的转录调节因子的过程中，我们鉴定了AUF 1。ENK是一种肽类神经递质，在成人大脑中表现出精确的细胞特异性表达。已知AUF 1（也称为异质核核糖核蛋白D）通过改变富含AU的mRNA的稳定性来调节基因表达。我们在这里表明，在发育中的大脑中，AUF 1蛋白以时空定义的方式表达，p37和p40/42亚型与大鼠ENK（rENK）基因的AT丰富的双链（ds）DNA元件结合。这种富含AT的dsDNA序列作为顺式调节DNA元件，参与调节原代神经元培养物中ENK基因的细胞特异性表达。富含AT的dsDNA元件存在于大鼠、人和小鼠ENK基因的5'上游约2.5kb处。AUF 1蛋白在此显示为这些上游富含AT的DNA序列和rENK基因的TATA区域之间提供直接相互作用。双重免疫组化表明，在发育中的大脑中，AUF 1蛋白表达的增殖神经祖细胞和分化的神经元填充的大脑区域，这将不会表达ENK基因在成人，这表明抑制剂的作用，AUF 1蛋白在脑啡肽能分化。它们的亚核分布和与富含AT的DNA的相互作用表明，在发育中的大脑中，它们可以参与控制ENK基因的发育和细胞特异性表达的复杂的核调节机制。
During our search for transcriptional regulators that control the developmentally regulated expression of the enkephalin (ENK) gene, we identified AUF1. ENK, a peptide neurotransmitter, displays precise cell-specific expression in the adult brain. AUF1 (also known as heterogeneous nuclear ribonucleoprotein D) has been known to regulate gene expression through altering the stability of AU-rich mRNAs. We show here that in the developing brain AUF1 proteins are expressed in a spatiotemporally defined manner, and p37 and p40/42 isoforms bind to an AT-rich double-stranded (ds) DNA element of the rat ENK (rENK) gene. This AT-rich dsDNA sequence acts as a cis-regulatory DNA element and is involved in regulating the cell-specific expression of the ENK gene in primary neuronal cultures. The AT-rich dsDNA elements are present at similar to 2.5 kb 5' upstream of the rat, human, and mouse ENK genes. AUF1 proteins are shown here to provide direct interaction between these upstream AT-rich DNA sequences and the TATA region of the rENK gene. Double immunohistochemistry demonstrated that in the developing brain AUF1 proteins are expressed by proliferating neural progenitors and by differentiating neurons populating brain regions, which will not express the ENK gene in the adult, suggesting a repressor role for AUF1 proteins during enkephalinergic differentiation. Their subnuclear distribution and interactions with AT-rich DNA suggest that in the developing brain they can be involved in complex nuclear regulatory mechanisms controlling the development- and cell-specific expression of the ENK gene.