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Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells

Oncogene volume 27, pages 1135–1141 (2008)Cite this article

Abstract

Persistent inhibition of telomerase induces a severe telomere shortening in human T-cell leukemia virus type-1-infected cells which signals a DNA double-strand break damage response, formation of telomere dysfunction-induced foci and activates the ATM pathway. In turn, activation of ATM and its downstream effectors led to an increased phosphorylation and acetylation on specific residues of p53 known to be involved in transcriptional activation. Disruption of Mdm2–p53 complexes coupled with increased proteasomal degradation of MDMX further enhanced reactivation of p53 transcription, ultimately leading to senescence of tumor cells. Induction of senescence in these T-cells was associated with an increased expression of p21, p16 and activation of GSK3β. Our results support the cancer–aging model and demonstrate that the halt of aging in cancer cells can be reversed through reactivation of p53.

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Acknowledgements

We would like to thank Dr G Lozano (University of Texas MD Anderson Cancer Center) for providing MDMX−/−, p53−/− MEF cells; Dr J Chen (H Lee Moffitt Cancer Center, Tampa, FL, USA) for MDMX expression plasmid and Diane L Persons, MD (University of Kansas Medical Center) for cytogenetic studies. This work was supported by grant R01CA106258 from the National Cancer Institute to C Nicot.

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  1. Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, Kansas City, KS, USA

    A Datta & C Nicot

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  1. A Datta
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Correspondence to C Nicot.

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Datta, A., Nicot, C. Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells. Oncogene 27, 1135–1141 (2008). https://doi.org/10.1038/sj.onc.1210718

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