The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1
The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1
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DOI：
10.1093/hmg/ddm325
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发表时间：
2008-02-14
影响因子：
3.5
通讯作者：
Gauthier, Benoit R.
中科院分区：
文献类型：
--
作者：
Brun, Thierry;He, Kai Hui Hu;Gauthier, Benoit R.
我们先前证明了转录因子Pax4对于大鼠胰岛中的β细胞复制和生存是重要的。在此，我们研究了Pax4在非糖尿病和糖尿病供者胰岛中的表达，以及有丝分裂原、葡萄糖和胰岛素GLP-1对Pax4的调节，并评价了Pax4对人胰岛增殖的影响。Pax4在2型糖尿病供者来源的胰岛中表达增加，与高血糖相关。对非糖尿病胰岛的体外研究表明，葡萄糖、β细胞蛋白、激活素A、GLP-1和胰岛素可增加Pax4的mRNA水平。葡萄糖诱导的Pax4表达可被LY294002、PD98050或H89抑制剂阻断。令人惊讶的是，Pax4表达的增加并没有促使人类胰岛细胞复制激增。此外，增殖标记基因Id2的表达没有变化。腺病毒介导的人Pax4表达使人胰岛细胞中Bclxl的表达略有增加，而Id2的转录水平和细胞复制没有变化。相反，小鼠Pax4的过表达诱导了人胰岛细胞的增殖。5-氮-2‘-脱氧胞苷处理胰岛诱导Pax4，但不刺激Bclxl和Id2的表达。人的Pax4DNA结合活性低于小鼠的同源物。因此，人类Pax4基因的表达受到表观遗传学的调控，并通过多条信号通路的协同作用受到生理刺激的诱导。然而，它不能启动转录复制程序，可能是由于蛋白质的翻译后修饰。后者强调了人类和啮齿动物胰岛生理学之间的根本差异，并强调了在人体组织中验证用动物模型获得的结果的重要性。
We previously demonstrated that the transcription factor Pax4 is important for beta-cell replication and survival in rat islets. Herein, we investigate Pax4 expression in islets of non-diabetic and diabetic donors, its regulation by mitogens, glucose and the incretin GLP-1 and evaluate its effect on human islet proliferation. Pax4 expression was increased in islets derived from Type 2 diabetic donors correlating with hyperglycaemia. In vitro studies on non diabetic islets demonstrated that glucose, betacellulin, activin A, GLP-1 and insulin increased Pax4 mRNA levels. Glucose-induced Pax4 expression was abolished by the inhibitors LY294002, PD98050 or H89. Surprisingly, increases in Pax4 expression did not prompt a surge in human islet cell replication. Furthermore, expression of the proliferation marker gene Id2 remained unaltered. Adenoviral-mediated expression of human Pax4 resulted in a small increase in Bcl-xL expression while Id2 transcript levels and cell replication were unchanged in human islets. In contrast, overexpression of mouse Pax4 induced human islet cell proliferation. Treatment of islets with 5-Aza-2'-deoxycytidine induced Pax4 without stimulating Bcl-xL and Id2 expression. Human Pax4 DNA binding activity was found to be lower than that of the mouse homologue. Thus, human pax4 gene expression is epigenetically regulated and induced by physiological stimuli through the concerted action of multiple signalling pathways. However, it is unable to initiate the transcriptional replication program likely due to post-translational modifications of the protein. The latter highlights fundamental differences between human and rodent islet physiology and emphasizes the importance of validating results obtained with animal models in human tissues.