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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Transcription factor EGR-1 transactivates the MMP1 gene promoter in response to TNFα in HaCaT keratinocytes

  • Yeo, Hyunjin (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Lee, Jeong Yeon (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Kim, JuHwan (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Ahn, Sung Shin (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Jeong, Jeong You (Cancer and Metabolism Institute, Konkuk University) ;
  • Choi, Ji Hye (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Lee, Young Han (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University) ;
  • Shin, Soon Young (Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University)
  • Received : 2019.11.21
  • Accepted : 2020.01.06
  • Published : 2020.06.30
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Abstract

Matrix metalloproteinase 1 (MMP-1), a calcium-dependent zinccontaining collagenase, is involved in the initial degradation of native fibrillar collagen. Tissue necrosis factor-alpha (TNFα) 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 TNFα and plays a critical role in tissue remodeling and skin aging processes. However, the regulation of the MMP1 gene by TNFα is not fully understood. We aimed to find additional cis-acting elements involved in the regulation of TNFα-induced MMP1 gene transcription in addition to the nuclear factor-kappa B (NF-κB) 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 (EGR-1)-binding sequence (EBS) in the proximal region for proper transcription by TNFα. Ectopic expression of EGR-1, a zinc-finger transcription factor that binds to G-C rich sequences, stimulated MMP1 promoter activity. The silencing of EGR-1 by RNA interference reduced TNFα-induced MMP-1 expression. EGR-1 directly binds to the proximal region and transactivates the MMP1 gene promoter. Mutation of the EBS within the MMP1 promoter abolished EGR-1-mediated MMP-1 promoter activation. These data suggest that EGR-1 is required for TNFα-induced MMP1 transcriptional activation. In addition, we found that all three MAPKs, ERK1/2, JNK, and p38 kinase, mediate TNFα-induced MMP-1 expression via EGR-1 upregulation. These results suggest that EGR-1 may represent a good target for the development of pharmaceutical agents to reduce inflammation-induced MMP-1 expression.

Keywords

References

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