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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.

Author information

1
College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA.
2
Center for Cell Biology & Cancer Research, Albany Medical College, Albany, NY 12208, USA.
3
Pediatrics, Albany Medical College, Albany, NY 12208, USA.
4
College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA. Electronic address: jmelendez@albany.edu.

Abstract

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.

KEYWORDS:

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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