Abstract
Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, hTERT repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies.
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Acknowledgements
We thank P Jalinot and E Gilson for their critical review of this manuscript, C Pinatel, A Lançon, C Paul and MD Reynaud for technical assistance; KJ Wu and R Dalla-Favera for TERTLuc800, pMT2TMyc, SM and DM constructs; WC Greene for pCMV-Tax plasmid and P Jalinot for the Tax monoclonal antibody HY474. ASG is supported by the Centre Léon Bérard, FM by the Ministère de l'Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale and PR by the Ministère de l'Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale. This work was supported by grants from the Ministère de l'Éducation Nationale, de la Recherche et de la Technologie (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires), from the Association pour la Recherche sur le Cancer, from the Fondation Contre la Leucémie and from the comité départemental de la Saône et Loire de la Ligue Nationale Contre le Cancer.
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Gabet, AS., Mortreux, F., Charneau, P. et al. Inactivation of hTERT transcription by Tax. Oncogene 22, 3734–3741 (2003). https://doi.org/10.1038/sj.onc.1206468
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DOI: https://doi.org/10.1038/sj.onc.1206468
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