Key Laboratory of Human Functional Genomics of Jiangsu Province, Clinical Diabetes Centre of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China.
Endocrinology. 2011 May;152(5):1779-88. doi: 10.1210/en.2010-1048. Epub 2011 Mar 8.
Transcription factors forkhead box (Fox)O1 and pancreatic and duodenal homeobox-1 (PDX-1) are involved in dexamethasone (DEX)-induced dysfunction in pancreatic β-cells. However, the molecular mechanism underlying the regulation of FoxO1 and PDX-1 expression in β-cells treated with DEX is not fully understood. In this study, we found that DEX markedly increased FoxO1 mRNA and protein expression, whereas it decreased PDX-1 mRNA and protein expression in a dose- and time-dependent manner. Further study showed that FoxA2 was involved in regulation of FoxO1 and PDX-1 expression in DEX-induced pancreatic β-cells dysfunction. Interestingly, we demonstrated for the first time that FoxA2 could bind to the FoxO1 gene promoter and positively regulate FoxO1 expression. Moreover, we found that DEX increased the activity of FoxA2 binding to the FoxO1 promoter but decreased the activity of FoxA2 binding to the PDX-1 promoter of RINm5F cells. Knockdown of FoxA2 by RNA interference inhibited FoxO1 expression and restored PDX-1 expression in pancreatic β-cells treated with DEX. However, DEX had no effect on the expression of FoxA2. Together, the results of the present study demonstrated that FoxA2 could dynamically regulate FoxO1 and PDX-1 expression in pancreatic β-cells treated with DEX, which provides new important information on the transcriptional regulation of FoxO1 and PDX-1 in DEX-induced pancreatic β-cells. Inhibition of FoxA2 can effectively protect β-cells against DEX-induced dysfunction.
转录因子叉头框 (Fox)O1 和胰腺十二指肠同源盒-1 (PDX-1) 参与了地塞米松 (DEX) 诱导的胰腺 β 细胞功能障碍。然而，DEX 处理的 β 细胞中 FoxO1 和 PDX-1 表达调控的分子机制尚不完全清楚。在本研究中，我们发现 DEX 以剂量和时间依赖的方式显著增加 FoxO1 mRNA 和蛋白表达，而降低 PDX-1 mRNA 和蛋白表达。进一步的研究表明，FoxA2 参与了 DEX 诱导的胰腺 β 细胞功能障碍中 FoxO1 和 PDX-1 表达的调节。有趣的是，我们首次证明 FoxA2 可以结合 FoxO1 基因启动子并正向调节 FoxO1 表达。此外，我们发现 DEX 增加了 FoxA2 结合到 RINm5F 细胞 FoxO1 启动子的活性，但降低了 FoxA2 结合到 PDX-1 启动子的活性。通过 RNA 干扰敲低 FoxA2 抑制了 DEX 处理的胰腺 β 细胞中 FoxO1 的表达，并恢复了 PDX-1 的表达。然而，DEX 对地塞米松处理的胰腺β细胞中 FoxA2 的表达没有影响。综上所述，本研究结果表明，FoxA2 可以在 DEX 处理的胰腺β细胞中动态调节 FoxO1 和 PDX-1 的表达，为 DEX 诱导的胰腺β细胞中 FoxO1 和 PDX-1 的转录调节提供了新的重要信息。抑制 FoxA2 可以有效保护β细胞免受 DEX 诱导的功能障碍。
