The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid.
Since mitochondrial dysfunction is a major source of oxidative stress in aged tissues, we asked whether the basal activities of stress response signaling pathway(s) are indicative of oxidative stress in aged tissues. To address this issue we asked whether: (a). aging affects the basal activity of the p38 MAPK stress signaling pathway; (b). the p38 MAPK pathway is activated by 3-nitropropionic acid (3-NPA), an inhibitor of complex II (succinic dehydrogenase) and generator of reactive oxygen species (ROS); (c). aging affects the response of the p38 alpha signaling pathway to 3-NPA. Our studies have shown that the basal kinase activities of p38 alpha, its upstream activator, MKK3, and its downstream substrate, ATF-2, are elevated in livers of aged C57BL/6 male mice and that these kinase activities, which are induced by 3-NPA in young livers, do not occur in aged livers. Furthermore, although aging does not affect their protein pool levels there are specific increases in phosphorylation of threonine residues in the p38 alpha and ATF-2 catalytic sites that might account for the increased basal level kinase activities in the aged livers. Our studies suggest that failure to respond to 3-NPA may be a factor in the susceptibility of aged tissue to oxidative damage, and support our hypothesis that aged tissues (especially liver) develop a state of chronic stress even in the absence of a challenge.
Hsieh
Ching-Chyuan
CC
Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, 613 Basic Sci Bldg, Rt 0643, Galveston, TX 77555-0643, USA.
Papaconstantinou
John
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D013912:Threonine; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C015392:3-nitropropionic acid