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J. Biol. Chem., Vol. 278, Issue 30, 28026-28037, July 25, 2003

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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^*

Niki Chondrogianni  , Fiona L. L. Stratford ¶, Ioannis P. Trougakos , Bertrand Friguet ||, A. Jennifer Rivett ¶ and Efstathios S. Gonos  **

From the National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece, the ^¶Department of Biochemistry, University of Bristol, School of Medical Sciences, Bristol, BS8 1TD, United Kingdom, and the ^||Université Denis Diderot-Paris 7, Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, 2 Place Jussieu, Paris 75005, France

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 20 S complex and subunits of the 19 S regulatory complex to be down-regulated in senescent cells. This is accompanied by a decrease in the level of both 20 S and 26 S 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 ₁ and ₅ subunits in WI38 established cell lines was shown to induce elevated expression levels of ₁ subunit in ₅ 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 toward a better understanding of proteasome regulation.

Received for publication, January 30, 2003 , and in revised form, April 30, 2003.

^* This work was supported in part by European Union QLRT "Protage" Grant QLK6-CT1999-02193 (to B. F., A. J. R., and E. S. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Ph.D. fellowship from the Bodosaki Foundation.

^** To whom correspondence should be addressed. Tel.: 30-210-7273756; Fax: 30-210-7273677; E-mail: sgonos{at}eie.gr.

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