Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase.
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.
Dasgupta
Jaya
J
Centers for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
Kar
Supriya
S
Liu
Rong
R
Joseph
Joy
J
Kalyanaraman
Balaraman
B
Remington
S James
SJ
Chen
Ceshi
C
Melendez
J Andres
JA
D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008665:Metalloporphyrins / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D008665:Metalloporphyrins; D016877:Oxidants; D017382:Reactive Oxygen Species; C474019:tetrakis(4-benzoic acid)porphyriniron(III); D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D020781:Matrix Metalloproteinase 1; D010100:Oxygen