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Transcription factor EGR1 transactivates the MMP1 gene promoter in response to TNFメ in HaCaT keratinocytes
Hyunjin Yeo1, Jeong Yeon Lee1, JuHwan Kim1, Young Han Lee1, SoonYoung Shin1,*
1Department of Biological Sciences, Konkuk University
Abstract
Matrix metalloproteinase 1 (MMP-1), a calcium-dependent zinc-containing collagenase, is involved in the initial degradation of native fibrillar collagen. Tissue necrosis factor-alpha (TNFメ) is a pro-inflammatory cytokine that is rapidly produced by dermal fibroblasts, monocytes/macrophages, and keratinocytes and regulates inflammation and damaged-tissue remodeling. MMP-1 is induced by TNFメ and plays a critical role in tissue remodeling and skin aging processes. However, the regulation of the MMP1 gene by TNFメ is not fully understood. We aimed to find additional cis-acting elements involved in the regulation of TNFメ-induced MMP1 gene transcription in addition to the nuclear factor-kappa B (NF-リB) and activator protein 1 (AP1) sites. Assessments of the 5∏-regulatory region of the MMP1 gene, using a series of deletion constructs, revealed the requirement of the early growth response protein 1 (EGR1)-binding sequence (EBS) in the proximal region for proper transcription by TNFメ. Ectopic expression of EGR1, a zinc-finger transcription factor that binds to G-C rich sequences, stimulated MMP1 promoter activity. The silencing of EGR1 by RNA interference reduced TNFメ-induced MMP-1 expression. EGR1 directly binds to the proximal region and transactivates the MMP1 gene promoter. Mutation of the EBS within the MMP1 promoter abolished EGR1-mediated MMP-1 promoter activation. These data suggest that EGR1 is required for TNFメ-induced MMP1 transcriptional activation. In addition, we found that all three MAPKs, ERK1/2, JNK, and p38 kinase, mediate TNFメ-induced MMP-1 expression via EGR1 upregulation. These results suggest that EGR1 may represent a good target for the development of pharmaceutical agents to reduce inflammation-induced MMP-1 expression.
Abstract, Accepted Manuscript(in press) [Submitted on November 21, 2019, Accepted on January 6, 2020]
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