Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids
Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids
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Cidea 是调节乳腺乳脂分泌的重要转录共激活因子
DOI：
10.1038/nm.2614
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发表时间：
2012-02-01
期刊：
影响因子：
82.9
通讯作者：
Li, Peng
中科院分区：
文献类型：
--
作者：
Wang, Wenshan;Lv, Na;Li, Peng
哺乳期乳腺分泌足够的脂质对哺乳动物后代的生存至关重要。然而，人们对这一过程的机制知之甚少。在这里，我们表明，Cidea是在高水平表达的哺乳期乳腺和它的缺陷导致过早的幼崽死亡的结果，严重减少牛奶脂质。此外，黄嘌呤氧化还原酶（XOR）的表达，一个重要的因素，牛奶脂质分泌，是显着降低在Cidea缺陷的乳腺。相反，异位Cidea表达诱导XOR的表达并增强体内脂质分泌。出乎意料的是，由于Cidea迄今为止一直被认为是一种细胞质蛋白，我们在细胞核中检测到它，并发现它与乳腺上皮细胞中的转录因子CCAAT/增强子结合蛋白β（C/EBP β）发生物理相互作用。我们还观察到Cidea通过促进C/EBP β与编码XOR的Xdh基因的启动子的结合以及HDAC 1与Xdh基因的启动子的解离来诱导XOR表达。最后，我们发现Fsp 27，另一个锡德家族蛋白，在细胞核中被检测到，并与C/EBP β相互作用，以调节脂肪细胞中C/EBP β下游基因子集的表达。因此，Cidea在乳腺中作为一种以前未知的C/EBP β转录共激活因子，控制脂质分泌和幼仔存活。
Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein beta (C/EBP beta) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBP beta onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBP beta to regulate expression of a subset of C/EBP beta downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBP beta in mammary glands to control lipid secretion and pup survival.