Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery
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 control...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
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| Series: | Inflammation and Regeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41232-023-00290-6 |
| _version_ | 1797577481091284992 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kenly Wuputra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T22:09:52Z |
| format | Article |
| id | doaj.art-f50a183d230244a7b496aebd1acd211c |
| institution | Directory Open Access Journal |
| issn | 1880-8190 |
| language | English |
| last_indexed | 2024-03-10T22:09:52Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Inflammation and Regeneration |
| spelling | doaj.art-f50a183d230244a7b496aebd1acd211c2023-11-19T12:41:10ZengBMCInflammation and Regeneration1880-81902023-08-0143112510.1186/s41232-023-00290-6Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene batteryKenly Wuputra0Ming-Ho Tsai1Kohsuke Kato2Chia-Chen Ku3Jia-Bin Pan4Ya-Han Yang5Shigeo Saito6Chun-Chieh Wu7Ying-Chu Lin8Kuang-Hung Cheng9Kung-Kai Kuo10Michiya Noguchi11Yukio Nakamura12Tohru Yoshioka13Deng-Chyang Wu14Chang-Shen Lin15Kazunari K. Yokoyama16Graduate Institute of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, Kaohsiung Medical UniversityDepartment of Infection Biology, Graduate School of Comprehensive Human Sciences, the University of TsukubaGraduate Institute of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, Kaohsiung Medical UniversityRegenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical UniversitySaito Laboratory of Cell TechnologyDepartment of Pathology, Kaohsiung Medical University HospitalSchool of Dentistry, Kaohsiung Medical UniversityDepartment of Biological Sciences, National Sun Yat-Sen UniversityRegenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical UniversityCell Engineering Division, BioResource Research CenterCell Engineering Division, BioResource Research CenterGraduate Institute of Medicine, Kaohsiung Medical UniversityRegenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical UniversityGraduate Institute of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, Kaohsiung Medical UniversityAbstract 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.https://doi.org/10.1186/s41232-023-00290-6AntioxidationAryl hydrocarbon receptorDioxin responsive elementNuclear factor (erythroid-derived 2)-like 2 transcription factorJun dimerization protein 2Oxidative stress |
| spellingShingle | 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 Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery Inflammation and Regeneration Antioxidation Aryl hydrocarbon receptor Dioxin responsive element Nuclear factor (erythroid-derived 2)-like 2 transcription factor Jun dimerization protein 2 Oxidative stress |
| title | Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery |
| title_full | Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery |
| title_fullStr | Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery |
| title_full_unstemmed | Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery |
| title_short | Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery |
| title_sort | jdp2 is a spatiotemporal transcriptional activator of the ahr via the nrf2 gene battery |
| topic | Antioxidation Aryl hydrocarbon receptor Dioxin responsive element Nuclear factor (erythroid-derived 2)-like 2 transcription factor Jun dimerization protein 2 Oxidative stress |
| url | https://doi.org/10.1186/s41232-023-00290-6 |
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