Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase. J Cell Physiol 2010 Oct;225(1):52-62
Date
07/22/2010Pubmed ID
20648623Pubmed Central ID
PMC2913426DOI
10.1002/jcp.22193Scopus ID
2-s2.0-77956555183 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
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.
Author List
Dasgupta J, Kar S, Liu R, Joseph J, Kalyanaraman B, Remington SJ, Chen C, Melendez JAAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell LineCellular Senescence
Dual Specificity Phosphatase 1
Fibroblasts
Green Fluorescent Proteins
Humans
Hydrogen Peroxide
JNK Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
Matrix Metalloproteinase 1
Metalloporphyrins
Oxidants
Oxidation-Reduction
Oxidative Stress
Oxygen
Reactive Oxygen Species
