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Free Radic Biol Med. 2014 Sep;74:99-107. doi: 10.1016/j.freeradbiomed.2014.06.017. Epub 2014 Jun 25.

Redox-sensitive gene-regulatory events controlling aberrant matrix metalloproteinase-1 expression.

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College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA.
Center for Cell Biology & Cancer Research, Albany Medical College, Albany, NY 12208, USA.
Pediatrics, Albany Medical College, Albany, NY 12208, USA.
College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA. Electronic address:


Aberrant matrix metalloproteinase-1 (MMP-1) expression contributes to the pathogenesis of many degenerative disease processes that are associated with increased oxidative damage or stress. We and others have established that shifts in steady-state H2O2 production resulting from enforced antioxidant gene expression, senescence, or UV irradiation control MMP-1 expression. Here we establish that histone deacetylase-2 (HDAC2) protein levels and its occupancy of the MMP-1 promoter are decreased in response to enforced manganese superoxide dismutase (Sod2) expression. Inhibition of HDAC activity further accentuates the redox-dependent expression of MMP-1. Sod2-dependent decreases in HDAC2 are associated with increases in a proteasome-sensitive pool of ubiquitinylated HDAC2 and MMP-1-specific histone H3 acetylation. Sod2 overexpression also enhanced recruitment of Ets-1, c-Jun, c-Fos, and the histone acetyltransferase PCAF to the distal and proximal regions of the MMP-1 promoter. Furthermore, the Sod2-dependent expression of MMP-1 can be reversed by silencing the transcriptional activator c-Jun. All of the above Sod2-dependent alterations are largely reversed by catalase coexpression, indicating that the redox control of MMP-1 is H2O2-dependent. These findings identify a novel redox regulation of MMP-1 transcription that involves site-specific promoter recruitment of both activating factors and chromatin-modifying enzymes, which converge to maximally drive MMP-1 gene expression.


Acetylation; Epigenetic modification; Free radicals; Histone deacetylase-2; Hydrogen peroxide; Manganese superoxide dismutase; Matrix metalloproteinase-1; Oxidative stress; Redox-dependent; Steady-state H(2)O(2) concentration

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