1. ¹Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2. ²Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr JN Brady, Virus Tumor Biology Section, National Cancer Institute, Laboratory of Cellular Oncology, Building 41/B201, 41 Medlars Dr, 9000 Rockville Pike, Bethesda, MD 20892, USA. E-mail: bradyj@exchange.nih.gov

Received 6 May 2005; Revised 27 July 2005; Accepted 27 July 2005; Published online 12 September 2005.

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 -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.