TY - JOUR
T1 - Decreased extracellular-signal-regulated kinase and increased stress-activated MAP kinase activities in aged human skin in vivo
AU - Chung, J. H.
AU - Kang, S.
AU - Varani, J.
AU - Lin, J.
AU - Fisher, G. J.
AU - Voorhees, J. J.
N1 - Funding Information:
The authors thank Suzan Rehbine and Carolyn Petersen for tissue procurement, Laura VanGoor for graphics preparation, Ted Hamilton for statistical analysis, and Anne Chapple for editorial assistance. This work was supported in part by the Babcock Endowment for Dermatological Research and a grant from the Johnson & Johnson Corporation.
PY - 2000
Y1 - 2000
N2 - The ability of human skin to rejuvenate itself diminishes with the passage of time, resulting in increased fragility. This increased fragility reflects both reduced growth of skin cells and loss of collagenous connective tissue. Oxidative damage plays a central role in cellular aging. Cellular responses to growth signals and oxidative stress are mediated, in part, by growth-factor-activated and stress-activated MAP kinases. We report here that the extracellular-signal-regulated MAP kinase pathway is reduced and the stress-activated MAP kinase pathway is increased in old, compared with young, human skin in vivo. Extracellular-signal-regulated kinase activity was 45% lower in old skin (mean age 84.3 y) relative to young skin (mean age 23.8 y). This lower extracellular-signal-regulated kinase activity resulted from reduced activation, since total extracellular-signal-regulated kinase protein levels did not differ between young and old skin, whereas phosphorylated (i.e., activated) extracellular-signal-regulated kinase protein was reduced 60% in old skin. Cyclin D2, which is regulated by extracellular-signal-regulated kinase and functions to promote cell cycle progression, was reduced 50% in old skin compared with young skin. In contrast, stress-activated MAP kinase activity was elevated 3.4-fold in old skin compared with young skin. This increased activity resulted from enhanced activation, since total stress-activated MAP kinase protein levels were similar in old and young skin. Transcription factor c-Jun, which is activated by stress-activated MAP kinases and promotes expression of connective-tissue-degrading matrix metalloproteinases, was elevated 2-fold in old skin compared with young skin. Treatment of old skin with vitamin A (retinol) for 7 d stimulated extracellular-signal-regulated kinase activity, consistent with its demonstrated ability to stimulate cell growth in old human skin. Taken together, these data indicate that alterations in MAP kinase activities play a key role in the pathophysiology of human skin aging.
AB - The ability of human skin to rejuvenate itself diminishes with the passage of time, resulting in increased fragility. This increased fragility reflects both reduced growth of skin cells and loss of collagenous connective tissue. Oxidative damage plays a central role in cellular aging. Cellular responses to growth signals and oxidative stress are mediated, in part, by growth-factor-activated and stress-activated MAP kinases. We report here that the extracellular-signal-regulated MAP kinase pathway is reduced and the stress-activated MAP kinase pathway is increased in old, compared with young, human skin in vivo. Extracellular-signal-regulated kinase activity was 45% lower in old skin (mean age 84.3 y) relative to young skin (mean age 23.8 y). This lower extracellular-signal-regulated kinase activity resulted from reduced activation, since total extracellular-signal-regulated kinase protein levels did not differ between young and old skin, whereas phosphorylated (i.e., activated) extracellular-signal-regulated kinase protein was reduced 60% in old skin. Cyclin D2, which is regulated by extracellular-signal-regulated kinase and functions to promote cell cycle progression, was reduced 50% in old skin compared with young skin. In contrast, stress-activated MAP kinase activity was elevated 3.4-fold in old skin compared with young skin. This increased activity resulted from enhanced activation, since total stress-activated MAP kinase protein levels were similar in old and young skin. Transcription factor c-Jun, which is activated by stress-activated MAP kinases and promotes expression of connective-tissue-degrading matrix metalloproteinases, was elevated 2-fold in old skin compared with young skin. Treatment of old skin with vitamin A (retinol) for 7 d stimulated extracellular-signal-regulated kinase activity, consistent with its demonstrated ability to stimulate cell growth in old human skin. Taken together, these data indicate that alterations in MAP kinase activities play a key role in the pathophysiology of human skin aging.
KW - C-Fos
KW - C-Jun
KW - Cyclin
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U2 - 10.1046/j.1523-1747.2000.00009.x
DO - 10.1046/j.1523-1747.2000.00009.x
M3 - Article
C2 - 10951233
AN - SCOPUS:0033889654
SN - 0022-202X
VL - 115
SP - 177
EP - 182
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -