Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Cell Mol Life Sci. 2010 Oct;67(20):3523-33. doi: 10.1007/s00018-010-0392-9. Epub 2010 May 28.
Aryl hydrocarbon receptor nuclear translocator (ARNT) binds to other basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins to form functional transcriptional complexes in order to regulate specific biological pathways. Here, we report a novel mechanism that upon EGF treatment, ARNT associated with non-bHLH-PAS transcription factors, c-Jun/Sp1, and regulated gene expression, through forming a c-Jun/ARNT/Sp1 complex and binding to the Sp1 site of the gene promoter. EGF-induced promoter activity and the mRNA level of 12(S)-lipoxygenase as well as the association between c-Jun and Sp1 were reduced by ARNT knockdown. Notably, dominant negative c-Jun mutant, TAM-67, blocked ARNT-mediated 12(S)-lipoxygenase expression, demonstrating that c-Jun was responsible for the transcriptional activation. Moreover, ARNT knockdown also inhibited other EGF-induced c-Jun/Sp1 mediated gene expression, such as p21( WAF1/CIP1 ). Our results reveal a novel mechanism by which ARNT acts as a modulator to bridge the c-Jun/Sp1 interaction and plays a role in EGF-mediated gene expression under normoxic conditions.
芳香烃受体核转位蛋白（ARNT）与其他基本螺旋-环-螺旋 PER/ARNT/Sim（bHLH-PAS）蛋白结合，形成功能性转录复合物，从而调节特定的生物途径。在这里，我们报告了一种新的机制，即在 EGF 处理下，ARNT 与非 bHLH-PAS 转录因子 c-Jun/Sp1 结合，并通过形成 c-Jun/ARNT/Sp1 复合物和结合基因启动子的 Sp1 位点来调节基因表达。ARNT 敲低降低了 EGF 诱导的启动子活性和 12(S)-脂氧合酶的 mRNA 水平，以及 c-Jun 和 Sp1 之间的关联。值得注意的是，显性负性 c-Jun 突变体 TAM-67 阻断了 ARNT 介导的 12(S)-脂氧合酶表达，表明 c-Jun 负责转录激活。此外，ARNT 敲低也抑制了其他 EGF 诱导的 c-Jun/Sp1 介导的基因表达，如 p21(WAF1/CIP1)。我们的研究结果揭示了一种新的机制，即 ARNT 作为一种调节剂，桥接 c-Jun/Sp1 相互作用，并在常氧条件下 EGF 介导的基因表达中发挥作用。
