Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part II - aging of nondividing cells

被引:133
作者
Sitte, N
Merker, K
Von Zglinicki, T
Davies, KJA
Grune, T
机构
[1] Univ So Calif, Ethel Percy Andrus Gerontol Ctr, Los Angeles, CA 90089 USA
[2] Univ So Calif, Div Mol Biol, Los Angeles, CA 90089 USA
[3] Humboldt Univ, Fac Med Charite, Clin Phys Med, D-10098 Berlin, Germany
[4] Humboldt Univ, Fac Med Charite, Clin Rehabil, D-10098 Berlin, Germany
[5] Humboldt Univ, Fac Med Charite, Inst Pathol, D-10098 Berlin, Germany
关键词
aging; cross-linked proteins; lysosomes; proteasome; protein oxidation; proteolysis; protein turnover; senescence;
D O I
10.1096/fj.00-0210com
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Oxidized/cross-linked intracellular protein materials, known as ceroid pigment, age pigment, or lipofuscin, accumulate in postmitotic tissues. It is unclear, however, whether diminishing proteolytic capacities play a role in the accumulation of such oxidized intracellular proteins. Previous studies revealed that the proteasome is responsible for the degradation of most oxidized soluble cytoplasmic and nuclear proteins and, we propose, for the prevention of such damage accumulations. The present investigation was undertaken to test the changes in protein turnover, proteasome activity, lysosome activity, and protein oxidation status during the aging of nondividing cells. Since the companion paper shows that both proteasome activity and the overall protein turnover decline during proliferative senescence whereas the accumulation of oxidized proteins increases significantly, we decided to use the same human BJ fibroblasts, this time at confluency, at different PD levels (including those that are essentially postmitotic) to investigate the same parameters under conditions where cells do not divide. We find that the activity of the cytosolic proteasome declines dramatically during senescence of nondividing BJ fibroblasts. The peptidyl-glutamyl-hydrolyzing activity was particularly affected. This decline in proteasome activity was accompanied by a decrease in the overall turnover of short-lived (radiolabeled) proteins in the nondividing BJ fibroblasts. On the other hand, no decrease in the actual cellular proteasome content, as judged by immunoblots, was found. The decline in the activity of the proteasome was also accompanied by an increased accumulation of oxidized proteins, especially of oxidized and cross-linked material. Unlike the loss of lysosomal function seen in our accompanying studies of proliferative senescence (1), however, the present study of hyperoxic senescence in nondividing cells actually revealed marked increases in lysosomal cathepsin activity in all but the very 'oldest' postmitotic cells. Our comparative studies of proliferating (1)and nonproliferating (this paper) human BJ fibroblasts reveal a good correlation between the accumulation of oxidized/cross-linked proteins and the decline in proteasome activity and overall cellular protein turnover during in vitro senescence, which may predict a causal relationship during actual cellular aging.
引用
收藏
页码:2503 / 2510
页数:8
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