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Human T-cell leukemia virus type 1 Tax attenuates γ-irradiation-induced apoptosis through physical interaction with Chk2

Oncogene volume 25, pages 438–447 (2006)Cite this article

Abstract

Checkpoint kinase 2 (Chk2) is known to mediate diverse cellular responses to genotoxic stress. The fundamental role of Chk2 is to regulate the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both hereditary and sporadic human cancers. We now present evidence that the human T-cell leukemia virus type-1 (HTLV-1) Tax protein directly interacts with Chk2 and the kinase activity of Chk2 is inhibited by Tax. The physical interaction of Chk2 and Tax was observed by co-immunoprecipitation assays in HTLV-1-infected T cells (C81) as well as GST pull-down assays using purified proteins. Binding and kinase activity inhibition studies with Tax deletion mutants indicated that at least two domains of Tax mediate the interaction with Chk2. We have analysed the functional consequence of de novo expression of Tax upon the cellular DNA-damage-induced apoptosis, which is mediated by Chk2. Using transient transfection and TUNEL assay, we found that γ-irradiation-induced apoptosis was decreased in 293T and HCT-116 (p53−/−) cells expressing HTLV-1 Tax. Our studies demonstrate an important potential target of Tax in cellular transformation.

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Acknowledgements

This research was supported by the intramural Research Program of the NIH, National Cancer Institute. We thank the FACS and Image core facility of CCR, NCI, NIH for flow cytometry analysis and confocal microscopy, respectively. We also thank Drs Bert Vogelstein and Fred Bunz for providing HCT-116 p21+/+ and p53−/− cell lines.

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Authors and Affiliations

  1. Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    H U Park, S-J Jeong & J N Brady

  2. Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    J-H Jeong & J H Chung

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  1. H U Park
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Correspondence to J N Brady.

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Park, H., Jeong, SJ., Jeong, JH. et al. Human T-cell leukemia virus type 1 Tax attenuates γ-irradiation-induced apoptosis through physical interaction with Chk2. Oncogene 25, 438–447 (2006). https://doi.org/10.1038/sj.onc.1209059

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