Manganese Superoxide Dismutase Signals Matrix Metalloproteinase Expression via H2O2-dependent ERK1/2 Activation

Aparna C. Ranganathan, Kristin K. Nelson, Ana M. Rodriguez, Kwi Hye Kim, Grant B. Tower, Joni L. Rutter, Constante E. Brinckerhoff, Ting Ting Huang, Charles J. Epstein, John J. Jeffrey, J. Andres Melendez

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O2-. at near-diffusion limiting rates and is the only antioxidant enzyme whose expression is regulated by numerous stimuli. Here it is shown that Sod2 also serves as a source of the intracellular signaling molecule H2O2. Sod2-dependent increases in the steady-state levels of H2O2 led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H2O 2-detoxifying enzyme, catalase. In addition, a single nucleotide polymorphism has recently been identified (1G/2G) at base pair -1607 that creates an Ets site adjacent to an AP-1 site at base pair -1602 and has been shown to dramatically enhance transcription of the MMP-1 promoter. Luciferase promoter constructs containing either the 1G or 2G variation were 25- or 1000-fold more active when transiently transfected into Sod2-overexpressing cell lines, respectively. The levels of MMP-2, -3, and -7 were also increased in the Sod2-overexpressing cell lines, suggesting that Sod2 may function as a "global" redox regulator of MMP expression. In addition, Sod2 -/+ mouse embryonic fibroblasts failed to respond to the cytokine-mediated induction of the murine functional analog of MMP-1, MMP-13. This study provides evidence that the modulation of Sod2 activity by a wide array of pathogenic and inflammatory stimuli may be utilized by the cell as a primary signaling mechanism leading to matrix metalloproteinase expression.

Original languageEnglish (US)
Pages (from-to)14264-14270
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number17
DOIs
StatePublished - Apr 27 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ranganathan, A. C., Nelson, K. K., Rodriguez, A. M., Kim, K. H., Tower, G. B., Rutter, J. L., Brinckerhoff, C. E., Huang, T. T., Epstein, C. J., Jeffrey, J. J., & Melendez, J. A. (2001). Manganese Superoxide Dismutase Signals Matrix Metalloproteinase Expression via H2O2-dependent ERK1/2 Activation. Journal of Biological Chemistry, 276(17), 14264-14270. https://doi.org/10.1074/jbc.M100199200