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Published on: July 3, 2015
Human T-cell leukemia virus type 1 Tax attenuates gamma-irradiation-induced apoptosis through physical interaction
H U Park1, S-J Jeong, J-H Jeong
1Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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 gamma-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.
Insights
Human T-cell leukemia virus type-1 Tax protein interacts with and inhibits Checkpoint kinase 2 (Chk2). This interaction reduces DNA-damage-induced apoptosis, suggesting Tax targets Chk2 in cellular transformation and cancer development.
Area of Science:
- Molecular Biology
- Virology
- Cell Biology
Background:
- Checkpoint kinase 2 (Chk2) is crucial for cellular responses to genotoxic stress, regulating DNA repair, cell-cycle progression, and apoptosis.
- Defects in Chk2 are implicated in hereditary and sporadic human cancers.
- Human T-cell leukemia virus type-1 (HTLV-1) is a retrovirus associated with certain cancers.
Purpose of the Study:
- To investigate the interaction between HTLV-1 Tax protein and Chk2.
- To determine the functional consequences of this interaction on DNA-damage-induced apoptosis.
Main Methods:
- Co-immunoprecipitation assays in HTLV-1-infected T cells.
- GST pull-down assays with purified proteins.
- Analysis of Tax deletion mutants for binding and kinase activity.
- Transient transfection and TUNEL assays to assess apoptosis in Tax-expressing cells after gamma-irradiation.
Main Results:
- HTLV-1 Tax protein directly interacts with Chk2.
- Tax inhibits the kinase activity of Chk2.
- At least two domains of Tax are involved in Chk2 interaction.
- Expression of Tax decreases gamma-irradiation-induced apoptosis in 293T and HCT-116 (p53(-/-)) cells.
Conclusions:
- HTLV-1 Tax protein targets and inhibits Chk2, a key player in genome surveillance.
- This inhibition of Chk2 by Tax may contribute to cellular transformation and cancer development associated with HTLV-1 infection.
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