Redox-dependent matrix metalloproteinase-1 expression is regulated by XXXX through Ets and AP-1 promoter motifs.

@entity3334 @entity274 @entity12136 @entity26 @entity3493 @entity1178 @entity4675 @entity669 @entity1366 @entity734
Reactive @entity26 species have been shown to play an important role in the regulation of distinct signaling cascades, many of which act upon the production of matrix metalloproteinases (MMP). Using a series of redox-engineered cell lines we have previously demonstrated that @entity3334 expression is sensitive to the alterations in the steady state production of @entity274 (Ranganathan, A. C., Nelson, K. K., Rodriguez, A. M., Kim, K. H., Tower, G. B., Rutter, J. L., Brinckerhoff, C. E., Epstein, C. J., Huang, T. T., Jeffrey, J. J., and Melendez, J. A. (2001) J. Biol. Chem. 276, 14264-14270). In the present study, we investigate the molecular mechanisms involved in the @entity274 -mediated induction of @entity3334 . Mutational analysis of an @entity3334 promoter indicates that both the single nucleotide polymorphism creating an Ets binding site at -1607 and a proximal AP-1 site at -1602 are required for maximal @entity274 -dependent transcription. The redox-sensitive @entity3334 protein expression requires activation of both @entity1366 and @entity4675 pathways. Importantly, @entity4675 signaling is largely responsible for the @entity274 sensitivity of the @entity3334 promoter, whereas @entity1366 contributes to both its basal and @entity274 @entity734 . @entity274 control of @entity12136 expression was @entity1366 -dependent whereas that of @entity1178 requires both @entity1366 and @entity4675 signaling. Chromatin immunoprecipitation assays indicate that binding of the histone acetyltransferase, @entity3493 , and the transcription factors @entity12136 and @entity1178 to the @entity3334 promoter is redox sensitive. The redox sensitivity of @entity3334 expression is also associated with an increase in the abundance of oxidatively inactivated protein- @entity669 phosphatases. Targeted cytosolic or mitochondrial scavenging of @entity274 prevented all of the aforementioned signals. These studies provide substantial insight into the mechanisms underlying the redox-dependent control of @entity3334 and may lead to the development of novel targeted antioxidant-based inhibitory therapies for controlling @entity3334 expression during degenerative disease processes.
