MATRIX METRALLOPROTEINASE-9 EXPRESSION IS COORDINATELY MODULATED BY THE KRE-M9 AND TPA RESPONSIVE ELEMENTS.

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To investigate the pathophysiological role of matrix metalloproteinase (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 TPA 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 rather than a transcription activator; we found several times higher transcriptional activity when the KRE-M9 element was mutated. In contrast, AP-1 proteins are shown to activate transcription by binding to the TRE which is located adjacent to the KRE-M9 element. Moreover, we found that the KRE-M9 binding protein potentially serves as a differentiation repressing factor (DRF)-1 as shown by the decrease in levels of this protein with differentiation. In addition, the KRE-M9 binding protein was able to bind to the TRE to some extent. These results indicate that the coordinate modulation of MMP-9 transcription via the TRE and the KRE-M9 element is important in epidermal and mesenchymal tissues.