Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery.

IF 5 3区 医学 Q2 IMMUNOLOGY
Kenly Wuputra, Ming-Ho Tsai, Kohsuke Kato, Chia-Chen Ku, Jia-Bin Pan, Ya-Han Yang, Shigeo Saito, Chun-Chieh Wu, Ying-Chu Lin, Kuang-Hung Cheng, Kung-Kai Kuo, Michiya Noguchi, Yukio Nakamura, Tohru Yoshioka, Deng-Chyang Wu, Chang-Shen Lin, Kazunari K Yokoyama
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Abstract Image

Abstract Image

Abstract Image

jp2是通过Nrf2基因电池激活AhR的时空转录激活因子。
背景:芳烃受体(AhR)和核因子(红细胞衍生2)样2 (Nrf2)信号传导之间的串扰被称为“AhR-Nrf2基因电池”,它们协同作用于解毒以支持细胞存活。Nrf2依赖的II期基因启动子通过AhR对相邻二恶英反应元件(DRE)和Nrf2对抗氧化反应元件(are)的协同募集来控制。AhR和Nrf2成员之间的分子相互作用,以及包括I期和II期基因复合物在内的每个靶标及其介质的调控尚不清楚。方法:采用敲低AhR- nrf2组成员和强制表达AhR- nrf2组成员的方法,研究AhR- nrf2轴与AhR启动子激活之间的分子相互作用。顺序免疫沉淀,染色质免疫沉淀和组织学被用来鉴定每个蛋白复合物募集到各自的顺式元件在AhR启动子。我们检测了肌动蛋白纤维分布、细胞扩散和侵袭,以确定野生型和Jdp2敲除细胞之间AhR-Jdp2轴的功能差异。在kras - trp53驱动的突变型胰腺肿瘤中,研究了Jdp2在AhR-Nrf2轴上可能的致瘤作用。结果:在转录水平上,AhR和Nrf2之间存在明显的串扰。AhR启动子被2,3,7,8-四氯二苯并-对二恶英(TCDD)等I相配体通过AhR- jdp2 - nrf2轴以时间和空间转录依赖的方式激活。Jdp2是DRE-和are -介导的转录的双功能激活剂。暴露于TCDD后,Jdp2在DRE激活AhR启动子,然后移动到ARE,激活启动子以增加活性氧(ROS)介导的功能,如正常细胞中的细胞扩散和侵袭,以及突变的kras - trp53驱动的胰腺肿瘤细胞的癌症消退。结论:Jdp2通过AhR-Jdp2- nrf2轴在AhR启动子激活中起着重要的时空作用。在Kras-Trp53突变型胰腺癌小鼠模型中,AhR发挥维持ROS平衡、细胞扩散、侵袭和癌症消退的作用。这些发现为jp2在氧化应激的稳态调节和解毒、炎症和癌症进展中的抗氧化反应中的作用提供了新的见解。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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