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* National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland;
Institut de Mathématiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
Division of Medical Genetics, Geneva University Hospital, Geneva, Switzerland; and
Swiss Institute of Bioinformatics, Lausanne, Switzerland
In human somatic cells, including T lymphocytes, telomeres progressively shorten with each cell division, eventually leading to a state of cellular senescence. Ectopic expression of telomerase results in the extension of their replicative life spans without inducing changes associated with transformation. However, it is yet unknown whether somatic cells that overexpress telomerase are physiologically indistinguishable from normal cells. Using CD8+ T lymphocyte clones overexpressing telomerase, we investigated the molecular mechanisms that regulate T cell proliferation. In this study, we show that early passage T cell clones transduced or not with human telomerase reverse transcriptase displayed identical growth rates upon mitogenic stimulation and no marked global changes in gene expression. Surprisingly, reduced proliferative responses were observed in human telomerase reverse transcriptase-transduced cells with extended life spans. These cells, despite maintaining high expression levels of genes involved in the cell cycle progression, also showed increased expression in several genes found in common with normal aging T lymphocytes. Strikingly, late passage T cells overexpressing telomerase accumulated the cyclin-dependent inhibitors p16Ink4a and p21Cip1 that have largely been associated with in vitro growth arrest. We conclude that alternative growth arrest mechanisms such as those mediated by p16Ink4a and p21Cip1 still remained intact and regulated the growth potential of cells independently of their telomere status.
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.
1 This study was sponsored and supported by the Swiss National Center of Competence in Research in Molecular Oncology, a research instrument of the Swiss National Science Foundation, a grant from the Arthur Andersen Foundation, and Swiss National Science Foundation Grant 3100A0-105929.
2 Address correspondence and reprint requests to Dr. Nathalie Rufer, Swiss Institute for Experimental Cancer Research, 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland. E-mail address: Nathalie.Rufer{at}isrec.ch
3 Abbreviations used in this paper: PD, population doubling; FISH, fluorescence in situ hybridization; HD, healthy donor; hTERT, human telomerase reverse transcriptase; 7-AAD, 7-aminoactinomycin D.
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