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Regulation of NFKBIZ gene promoter activity by STAT3, C/EBPβ, and STAT1.

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Title: Regulation of NFKBIZ gene promoter activity by STAT3, C/EBPβ, and STAT1.
Authors: Muromoto, Ryuta Browse this author →KAKEN DB
Sato, Ami Browse this author
Komori, Yuki Browse this author
Nariya, Kota Browse this author
Kitai, Yuichi Browse this author →KAKEN DB
Kashiwakura, Jun-Ichi Browse this author →KAKEN DB
Matsuda, Tadashi Browse this author →KAKEN DB
Keywords: Inflammation
Transcriptional regulation
Issue Date: 12-Jul-2022
Publisher: Academic Press
Journal Title: Biochemical and biophysical research communications
Volume: 613
Start Page: 61
End Page: 66
Publisher DOI: 10.1016/j.bbrc.2022.04.140
PMID: 35537286
Abstract: Interleukin-17A (IL-17A) is a cytokine that affects the functions of non-immune cells, including keratinocytes, and thereby amplifies immune responses. An IκB family protein IκB-ζ, encoded by the NFKBIZ gene, mediates IL-17A-induced inflammatory cellular responses. Previously we reported that a transcription factor STAT3 mediates the transcriptional induction of NFKBIZ through its binding to the specific binding site existing in the NFKBIZ promoter. However, it remains unclear how other transcription factors regulate NFKBIZ transcription. Here, we investigated the NFKBIZ promoter regulation by transcription factors C/EBPβ and STAT1 and revealed opposing roles of C/EBPβ and STAT1 in NFKBIZ transcription. We found that siRNA-mediated knockdown of C/EBPβ attenuates IL-17A-induced upregulation of NFKBIZ in the HaCaT cell line. A putative C/EBP-binding site is located adjacent to the STAT-binding site in the NFKBIZ promoter, the deletion of which abolished C/EBPβ-driven promoter activation in transient NFKBIZ promoter-luciferase assay. Deleting the STAT-binding site also led to a reduction in C/EBPβ-driven promoter activation, suggesting a cooperative action between C/EBP- and STAT-binding sites. Furthermore, Co-overexpression of STAT1 suppressed both C/EBPβ- and STAT3-driven NFKBIZ promoter activation independently of its tyrosine 701 phosphorylation. siRNA-mediated STAT1 knockdown augmented IκB-ζ induction in IL-17A-treated HaCaT cells, with enhanced expression of an IκB-ζ target gene DEFB4A. Together, these results indicate that both C/EBPβ and STAT3 are transcription factors that coordinately induce NFKBIZ promoter activation, indicating that STAT1 has an inhibitory role. Thus, these could be a fine-tuning mechanism of IL-17A-IκB-ζ-mediated cellular responses.
Rights: © 2022. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 室本 竜太

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