被称为“AhR-Nrf2基因电池”的芳香族碳氢受体（AhR）和核因子（红细胞源性2）类似物2（Nrf2）信号之间的相互作用，协同在解毒过程中起到支持细胞存活的作用。Nrf2依赖的第二阶段基因启动子，通过协调招募AhR至邻近的二恶英响应元素（DRE），和Nrf2至抗氧化反应元件（ARE）来进行控制。AhR与Nrf2成员之间的分子相互作用以及每个靶点的调节，包括第一和第二阶段基因复合物，以及它们的介导物，目前尚不清楚。我们用AhR-Nrf2电池成员的敲除和强制表达来研究AhR-Nrf2轴和AhR启动子激活之间的分子相互作用。采用顺序免疫沉淀、染色质免疫沉淀和组织学方法来确定每个蛋白质复合物招募到AhR启动子的相应顺式元素中。通过检测肌动蛋白纤维分布、细胞扩张和浸润，分析野生型和Jdp2基因敲除的细胞之间在AhR-Jdp2轴上的功能差异。在突变Kras-Trp53驱动的胰腺肿瘤中，观察Jdp2在AhR-Nrf2轴中的潜在致瘤作用。AhR和Nrf2之间的相互作用在转录水平上是明显的。AhR启动子以阶段I配体（如2,3,7,8-四氯代二苯并噻二唑）通过AhR-Jdp2-Nrf2轴的方式被激活，这是一个以时间和空间为依据的转录依赖过程。Jdp2是对于TCDD响应的DRE-和ARE介导的转录的双功能激活因子。在经历TCDD暴露后，Jdp2在DRE处激活AhR启动子，然后移动到ARE，在那里激活启动子以增加正常细胞中介导的反应性氧化物产生（ROS）的功能，例如细胞扩张和浸润，以及突变Kras-Trp53驱动的胰腺肿瘤中的癌症逆转。Jdp2在AhR启动子的激活中以一种时空方式发挥关键作用。AhR功能维持ROS平衡和细胞扩张、浸润以及在突变Kras-Trp53胰腺癌的小鼠模型中的癌症逆转。这些发现为Jdp2在氧化应激和解毒、炎症和癌症进展中的家庭调控提供了新的见解。 © 2023年。 日本炎症和再生学会。

Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the "AhR-Nrf2 gene battery", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood.Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors.Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells.Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.© 2023. Japanese Society of Inflammation and Regeneration.