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Reactive oxygen species control senescence‐associated matrix metalloproteinase‐1 through c‐Jun‐N‐terminal kinase
Author(s) -
Dasgupta Jaya,
Kar Supriya,
Liu Rong,
Joseph Joy,
Kalyanaraman Balaraman,
Remington S. James,
Chen Ceshi,
Melendez J. Andres
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22193
Subject(s) - matrix metalloproteinase , senescence , oxidative stress , reactive oxygen species , kinase , microbiology and biotechnology , phosphorylation , phosphatase , chemistry , c jun , downregulation and upregulation , signal transduction , redox , extracellular matrix , biochemistry , biology , transcription factor , gene , organic chemistry
The lifetime exposure of organisms to oxidative stress influences many aging processes which involve the turnover of the extracellular matrix. In this study, we identify the redox‐responsive molecular signals that drive senescence‐associated (SA) matrix metalloproteinase‐1 (MMP‐1) expression. Precise biochemical monitoring revealed that senescent fibroblasts increase steady‐state (H 2 O 2 ) 3.5‐fold (13.7–48.6 pM) relative to young cells. Restricting H 2 O 2 production through low O 2 exposure or by antioxidant treatments prevented SA increases in MMP‐1 expression. The H 2 O 2 ‐dependent control of SA MMP‐1 is attributed to sustained JNK activation and c‐jun recruitment to the MMP‐1 promoter. SA JNK activation corresponds to increases and decreases in the levels of its activating kinase (MKK‐4) and inhibitory phosphatase (MKP‐1), respectively. Enforced MKP‐1 expression negates SA increases in JNK phosphorylation and MMP‐1 production. Overall, these studies define redox‐sensitive signaling networks regulating SA MMP‐1 expression and link the free radical theory of aging to initiation of aberrant matrix turnover. J. Cell. Physiol. 225: 52–62, 2010. © 2010 Wiley‐Liss, Inc.