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Published on: March 30, 2022
Matrix metalloproteinase 9 expression is coordinately modulated by the KRE-M9 and
Takashi Kobayashi1, Jiro Kishimoto, Shunji Hattori
1Department of Dermatology/Clinical Biology of Extracellular Matrix, Chiba University School of Medicine, Chiba, Japan. tkobayas@faculty.chiba-u.jp
Abstract:
To investigate the pathophysiologic role of matrix metalloproteinase 9 (MMP-9), we analyzed the mechanism of its transcriptional regulation in keratinocytes and in HT1080 fibrosarcoma cells in culture. The KRE-M9 element, which is located between the 12-O-tetradecanoyl-phorbol-13-acetate responsive element (TRE) and the transcription initiation site in the MMP-9 promoter, is essential for MMP-9 transcription in the absence of the TRE. The KRE-M9 binding protein, however, is shown to be a repressor of transcription rather than an activator; we found several times higher transcriptional activity when the KRE-M9 element was mutated. In contrast, activator protein 1 proteins (AP-1) are shown to activate transcription of MMP-9 by binding to the TRE, which is located adjacent to the KRE-M9 element. Moreover, we found that the KRE-M9 binding protein could serve as a differentiation repressing factor 1 (DRF-1) as shown by the decrease in levels of this protein with differentiation. In addition, the TRE binding protein is able to bind to the KRE-M9 to some extent. These results indicate that the coordinated modulation of MMP-9 transcription via the TRE and the KRE-M9 elements is important in epidermal and mesenchymal tissues. Our findings could facilitate consideration of the molecular mechanism in a variety of pathophysiologic conditions with which MMP-9 is involved.
Insights
Matrix metalloproteinase 9 (MMP-9) transcription is regulated by the KRE-M9 element, which acts as a repressor, and the activator protein 1 (AP-1) binding to the TRE. This coordinated control is vital in skin and connective tissues.
Area of Science:
- Molecular biology
- Cell biology
- Biochemistry
Background:
- Matrix metalloproteinase 9 (MMP-9) plays a role in various pathophysiologic conditions.
- Understanding MMP-9 transcriptional regulation is crucial for studying diseases involving this enzyme.
Purpose of the Study:
- To investigate the transcriptional regulation mechanism of matrix metalloproteinase 9 (MMP-9).
- To analyze the function of the KRE-M9 element and its binding protein in MMP-9 gene expression.
Main Methods:
- Analysis of MMP-9 promoter activity in keratinocytes and HT1080 fibrosarcoma cells.
- Investigation of transcription factor binding to the KRE-M9 and TRE elements within the MMP-9 promoter.
- Assessment of protein levels in relation to cellular differentiation.
Main Results:
- The KRE-M9 element is essential for MMP-9 transcription, and its binding protein acts as a transcriptional repressor.
- Activator protein 1 (AP-1) proteins activate MMP-9 transcription by binding to the adjacent TRE element.
- The KRE-M9 binding protein functions as differentiation repressing factor 1 (DRF-1), with its levels decreasing during differentiation.
Conclusions:
- Coordinated modulation of MMP-9 transcription via TRE and KRE-M9 elements is important in epidermal and mesenchymal tissues.
- Findings provide insight into the molecular mechanisms underlying MMP-9 involvement in various pathophysiologic conditions.
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