The roles of ATF3 in glucose homeostasis - A transgenic mouse model with liver dysfunction and defects in endocrine pancreas
The roles of ATF3 in glucose homeostasis - A transgenic mouse model with liver dysfunction and defects in endocrine pancreas
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DOI：
10.1074/jbc.m100986200
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发表时间：
2001-08-03
影响因子：
4.8
通讯作者：
Hai, T
中科院分区：
文献类型：
--
作者：
Allen-Jennings, AE;Hartman, MG;Hai, T
激活转录因子3 （activated transcription factor 3, ATF3）是ATF/ camp反应元件结合蛋白家族的一员。它是一种转录抑制因子，在包括肝脏在内的多种组织中，应激信号诱导其相应基因的表达。在这篇报道中，我们证明了ATF3可以通过胰腺部分切除术、链脲佐菌素治疗和缺血再灌注诱导。此外，在培养的胰岛细胞中，氧化应激可诱导ATF3。有趣的是，在转甲状腺素启动子控制下，肝脏和胰腺中表达ATF3的转基因小鼠在葡萄糖稳态和围产期死亡率方面存在缺陷。我们提出的证据表明，肝脏中ATF3的表达抑制了编码糖异生酶的基因的表达。此外，胰腺中ATF3的表达导致胰腺内分泌异常，产生激素的细胞数量减少。胚胎分析表明，ATF3转基因基因在发育中的胰腺导管上皮中表达，并且转基因胰腺的有丝分裂细胞比非转基因胰腺少，这可能解释了内分泌细胞减少的原因。由于ATF3是一种应激诱导基因，这些小鼠可能为研究一些应激相关疾病的分子机制提供了模型。
Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcription factors. It is a transcriptional repressor, and the expression of its corresponding gene is induced by stress signals in a variety of tissues, including the liver. In this report, we demonstrate that ATF3 is induced in the pancreas by partial pancreatectomy, streptozotocin treatment, and ischemia coupled with reperfusion. Furthermore, ATF3 is induced in cultured islet cells by oxidative stress. Interestingly, transgenic mice expressing ATF3 in the liver and pancreas under the control of the transthyretin promoter have defects in glucose homeostasis and perinatal lethality. We present evidence that expression of ATF3 in the liver represses the expression of genes encoding gluconeogenic enzymes. Furthermore, expression of ATF3 in the pancreas leads to abnormal endocrine pancreas and reduced numbers of hormone-producing cells. Analyses of embryos indicated that the ATF3 transgene is expressed in the ductal epithelium in the developing pancreas, and the transgenic pancreas has fewer mitotic cells than the non-transgenic counterpart, providing a potential explanation for the reduction of endocrine cells. Because ATF3 is a stress-inducible gene, these mice may represent a model to investigate the molecular mechanisms for some stress-associated diseases.