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Papers In Press, published online ahead of print May 7, 2003
Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens 116 35
Corresponding Author: sgonos{at}eie.gr
Normal human fibroblasts undergo a limited number of divisions in culture and progressively they reach a state of irreversible growth arrest, a process termed as replicative senescence. The proteasome is the major cellular proteolytic machinery, the function of which is impaired during replicative senescence. However the exact causes of its malfunction in these conditions are unknown. Using WI38 fibroblasts as a model for cellular senescence we have observed reduced levels of proteasomal peptidase activities coupled with increased levels of both oxidized and ubiquitinated proteins in senescent cells. We have found the catalytic subunits of the 20S complex and subunits of the 19S regulatory complex to be down-regulated in senescent cells. This is accompanied by a decrease in the level of both 20S and 26S complexes. Partial inhibition of proteasomes in young cells caused by treatment with specific inhibitors induced a senescence-like phenotype, thus demonstrating the fundamental importance of the proteasome for retaining cellular maintenance and homeostasis. Stable overexpression of â1 and â5 subunits in WI38 established cell lines was shown to induce elevated expression levels of â1 subunit in â5 transfectants and vice-versa. Transfectants possess increased proteasome activities and most importantly, increased capacity to cope better with various stresses. In summary these data demonstrate the central role of the proteasome during cellular senescence and survival as well as provide insights towards a better understanding of proteasome regulation.
J. Biol. Chem, 10.1074/jbc.M301048200
Submitted on January 30, 2003
Revised on April 30, 2003
Accepted on May 7, 2003
Central role of the proteasome in senescence and survival of human fibroblasts: Induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation
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