Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1.
Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathological conditions. Here we addressed the question of whether isolated, unbalanced overexpression of the antioxidant enzyme manganese superoxide dismutase (Mn-SOD) may modulate signal transduction cascades, finally leading to connective tissue degradation, a hallmark in carcinogenesis and aging. Therefore, we generated stably Mn-SOD-overexpressing fibroblasts with an up to 4. 6-fold increase in Mn-SOD activity. The Mn-SOD-overexpressing cells revealed specific resistance to the superoxide anion (O-(2))-generating agent paraquat, whereas no resistance to UVA-generated oxidative stress was found. Treatment of the Mn-SOD-overexpressing cells with various ROS-generating systems resulted (due to the enhanced dismutation of superoxide anion to hydrogen peroxide) in an up to 9.5-fold increase in matrix-degrading metalloprotease-1 (MMP-1) mRNA levels. A similar increase in MMP-1 mRNA was also seen when the intracellular H(2)O(2) concentration was increased by the inhibition of different H(2)O(2)-detoxifying pathways. Furthermore, prooxidant conditions led to a strong induction of c-jun and c-fos mRNA levels resulting in a 4-fold higher transactivation of the transcription factor AP-1 in the Mn-SOD-overexpressing cells. Collectively, we have found that enhanced Mn-SOD activity, via an unbalanced H(2)O(2) overproduction and detoxification, induces MMP-1 mRNA levels, and this effect is at least partly mediated by the DNA recognition sequence AP-1.
Wenk
J
J
Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
Brenneisen
P
P
Wlaschek
M
M
Poswig
A
A
Briviba
K
K
Oberley
T D
TD
Scharffetter-Kochanek
K
K
D002460:Cell Line; D017364:Collagenases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016166:Free Radical Scavengers; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D017364:Collagenases; D020781:Matrix Metalloproteinase 1