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Molecular and Cellular Biology, June 2004, p. 5459-5474, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5459-5474.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

A. Satyanarayana,1 R. A. Greenberg,2 S. Schaetzlein,1 J. Buer,3,4 K. Masutomi,5 W. C. Hahn,5 S. Zimmermann,6 U. Martens,6 M. P. Manns,1 and K. L. Rudolph1*

Department of Gastroenterology, Hepatology, and Endocrinology,1 Department of Microbiology, Medical School Hannover, Hannover,3 Department of Cell Biology, GBF, Braunschweig,4 Department of Hematology/Oncology, Medical University Center Freiburg, Freiburg, Germany,6 Department of Cancer Biology,2 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts5

Received 6 November 2003/ Returned for modification 17 December 2003/ Accepted 12 March 2004

Replicative senescence is induced by critical telomere shortening and limits the proliferation of primary cells to a finite number of divisions. To characterize the activity status of the replicative senescence program in the context of cell cycle activity, we analyzed the senescence phenotypes and signaling pathways in quiescent and growth-stimulated primary human fibroblasts in vitro and liver cells in vivo. This study shows that replicative senescence signaling operates at a low level in cells with shortened telomeres but becomes fully activated when cells are stimulated to enter the cell cycle. This study also shows that the dysfunctional telomeres and nontelomeric DNA lesions in senescent cells do not elicit a DNA damage signal unless the cells are induced to enter the cell cycle by mitogen stimulation. The amplification of senescence signaling and DNA damage responses by mitogen stimulation in cells with shortened telomeres is mediated in part through the MEK/mitogen-activated protein kinase pathway. These findings have implications for the further understanding of replicative senescence and analysis of its role in vivo.

* Corresponding author. Mailing address: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Phone: 0049-511-532-3489. Fax: 0049-511-532-2021. E-mail: Rudolph.Lenhard{at}Mh-Hannover.de.

Molecular and Cellular Biology, June 2004, p. 5459-5474, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5459-5474.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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