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

Inflammation and Regeneration

Research Article

Yukio Nakamura¹  Michiya Noguchi¹  Kuang-Hung Cheng²  Kohsuke Kato³  Chun-Chieh Wu⁴  Tohru Yoshioka⁵  Chang-Shen Lin⁶  Chia-Chen Ku⁷  Kazunari K. Yokoyama⁷  Kenly Wuputra⁷  Jia-Bin Pan⁷  Ming-Ho Tsai⁷  Deng-Chyang Wu⁸  Kung-Kai Kuo⁹  Ya-Han Yang⁹  Shigeo Saito^1,10  Ying-Chu Lin^1,11 

[1] Cell Engineering Division, BioResource Research Center, 305-0074, Tsukuba, Ibaraki, Japan;Department of Biological Sciences, National Sun Yat-Sen University, 80424, Kaohsiung, Taiwan;Department of Infection Biology, Graduate School of Comprehensive Human Sciences, the University of Tsukuba, 305-8577, Tsukuba, Japan;Department of Pathology, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Graduate Institute of Medicine, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Graduate Institute of Medicine, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Department of Biological Sciences, National Sun Yat-Sen University, 80424, Kaohsiung, Taiwan;Graduate Institute of Medicine, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Cell Therapy and Research Center, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Cell Therapy and Research Center, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;Cell Therapy and Research Center, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 80756, Kaohsiung, Taiwan;Saito Laboratory of Cell Technology, 329-1571, Yaita, Tochigi, Japan;School of Dentistry, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;

关键词: Antioxidation;    Aryl hydrocarbon receptor;    Dioxin responsive element;    Nuclear factor (erythroid-derived 2)-like 2 transcription factor;    Jun dimerization protein 2;    Oxidative stress;    Reactive oxygen species;    Transcriptional regulation;   

DOI  :  10.1186/s41232-023-00290-6

 received in 2022-10-20, accepted in 2023-07-06,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCrosstalk 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.MethodsKnockdown 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.ResultsCrosstalk 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.ConclusionsJdp2 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.

【 授权许可】

CC BY   
© Japanese Society of Inflammation and Regeneration 2023

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