title: Redox-sensitive gene-regulatory events controlling aberrant matrix metalloproteinase-1 expression.
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.
authors: College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA.
authors: Toni R
authors: TR
authors: Bartling
authors: Center for Cell Biology & Cancer Research, Albany Medical College, Albany, NY 12208, USA.
authors: Sita
authors: S
authors: Subbaram
authors: College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA.
authors: Ryan R
authors: RR
authors: Clark
authors: College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA.
authors: Akshaya
authors: A
authors: Chandrasekaran
authors: Pediatrics, Albany Medical College, Albany, NY 12208, USA.
authors: Supriya
authors: S
authors: Kar
authors: College of Nanoscale Science and Engineering, State University of New York, Albany, NY 12203, USA. Electronic address: jmelendez@albany.edu.
authors: J Andres
authors: JA
authors: Melendez
mesh_terms: D002374:Catalase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics; D054875:Ubiquitination; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D056464:Histone Deacetylase 2; D006657:Histones; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
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