KMID : 0624620200530060323
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BMB Reports 2020 Volume.53 No. 6 p.323 ~ p.328
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Transcription factor EGR-1 transactivates the MMP1 gene promoter in response to TNF¥á in HaCaT keratinocytes
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Yeo Hyun-Jin
Lee Jeong-Yeon Kim Ju-Hwan Ahn Sung-Shin Jeong Jeong-You Choi Ji-Hye Lee Young-Han Shin Soon-Young
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Abstract
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Matrix metalloproteinase 1 (MMP-1), a calcium-dependent zinccontaining collagenase, is involved in the initial degradation of native fibrillar collagen. Tissue necrosis factor-alpha (TNF¥á) 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¥á and plays a critical role in tissue remodeling and skin aging processes. However, the regulation of the MMP1 gene by TNF¥á is not fully understood. We aimed to find additional cis-acting elements involved in the regulation of TNF¥á-induced MMP1 gene transcription in addition to the nuclear factor-kappa B (NF-¥êB) 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 TNF¥á. 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 TNF¥á-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 TNF¥á-induced MMP1 transcriptional activation. In addition, we found that all three MAPKs, ERK1/2, JNK, and p38 kinase, mediate TNF¥á-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.
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KEYWORD
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EGR-1, EGR-1-binding sequence, Gene promoter, Mitogen-activated protein kinase, MMP1, TNF¥á
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