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J. Biol. Chem., Vol. 279, Issue 33, 34332-34335, August 13, 2004

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Glutathione Regulates Telomerase Activity in 3T3 Fibroblasts^*

Consuelo Borrás, Juan M. Esteve, Juan R. Viña, Juan Sastre, José Viña, and Federico V. Pallardó¶

From the Department of Physiology and the Department of Biochemistry, School of Medicine, University of Valencia, 46010 Valencia, Spain

Changes in telomerase activity have been associated either with cancer, when activity is increased, or with cell cycle arrest when it is decreased. We report that glutathione, a physiological antioxidant present at high intracellular concentrations, regulates telomerase activity in cells in culture. Telomerase activity increases in 3T3 fibroblasts before exponential cell growth. The peak of telomerase activity takes place 24 h after plating and coincides with the maximum levels of glutathione in the cells. When cells are treated with buthionine sulfoximine, which decreases glutathione levels in cells, telomerase activity decreases by 60%, and cell growth is delayed. Glutathione depletion inhibits expression of E2F4 and Id2, which regulate the cell cycle. When glutathione levels are restored after incubation with glutathione monoethylester, telomerase activity and the cell cycle-related proteins return to control values. To discover the effect of glutathione redox status on the telomerase multicomplex structure, we incubated protein extracts from fibroblasts with different glutathione redox buffers. Telomerase activity is maximal under reduced conditions i.e. when the reduced/oxidized glutathione ratio is high. Consequently glutathione concentration parallels telomerase activity. These results underscore the main role of glutathione in the control of telomerase activity and of the cell cycle.

Received for publication, March 3, 2004 , and in revised form, June 3, 2004.

^* This work was supported by grants from Comision Interministerial de Ciencia y Tecnologia (BFI-2001-2849 (to J. R. V.) and PM 99/0148 and SAF2002/00885 (to F. V. P.)) and from Instituto de Salud Carlos III, RCMN (C03/08), Madrid, Spain. 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.

^¶ To whom correspondence should be addressed: Dept. of Physiology, University of Valencia, Avda. Blasco Ibáñez 17, 46010 Valencia, Spain. Tel.: 34-96-3864641; Fax: 34-96-3864642; E-mail: pallardo{at}uv.es.

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