Matrix metalloproteinase 9 expression is coordinately modulated by the KRE-M9 and 12-O-tetradecanoyl-phorbol-13-acetate responsive elements.
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.
Kobayashi
Takashi
T
Department of Dermatology/Clinical Biology of Extracellular Matrix, Chiba University School of Medicine, Chiba, Japan. tkobayas@faculty.chiba-u.jp
Kishimoto
Jiro
J
Hattori
Shunji
S
Wachi
Hiroshi
H
Shinkai
Hiroshi
H
Burgeson
Robert E
RE
D002273:Carcinogens; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005354:Fibrosarcoma; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology
D002273:Carcinogens; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate