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Human T-cell leukemia virus type 2 tax mutants that selectively abrogate NFkappaB or CREB/ATF activation fail to
T M Ross1, M Narayan, Z Y Fang
1Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Abstract:
Human T-cell leukemia virus (HTLV) Tax protein has been implicated in the HTLV oncogenic process, primarily due to its pleiotropic effects on cellular genes involved in growth regulation and cell cycle control. To date, several approaches attempting to correlate Tax activation of the CREB/activating transcription factor (ATF) or NFkappaB/Rel transcriptional activation pathway to cellular transformation have yielded conflicting results. In this study, we use a unique HTLV-2 provirus (HTLV(c-enh)) that replicates by a Tax-independent mechanism to directly assess the role of Tax transactivation in HTLV-mediated T-lymphocyte transformation. A panel of well-characterized tax-2 mutations is utilized to correlate the respective roles of the CREB/ATF or NFkappaB/Rel signaling pathway. Our results demonstrate that viruses expressing tax-2 mutations that selectively abrogate NFkappaB/Rel or CREB/ATF activation display distinct phenotypes but ultimately fail to transform primary human T lymphocytes. One conclusion consistent with our results is that the activation of NFkappaB/Rel provides a critical proliferative signal early in the cellular transformation process, whereas CREB/ATF activation is required to promote the fully transformed state. However, complete understanding will require correlation of Tax domains important in cellular transformation to those Tax domains important in the modulation of gene transcription, cell cycle control, induction of DNA damage, and other undefined activities.
Insights
The Human T-cell leukemia virus (HTLV) Tax protein
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- The Human T-cell leukemia virus (HTLV) Tax protein is linked to HTLV oncogenesis.
- Its effects on cell growth and cycle control genes are complex.
- Previous studies on Tax activation pathways (CREB/ATF, NFkappaB/Rel) and T-lymphocyte transformation have shown conflicting results.
Purpose of the Study:
- To directly assess the role of Tax transactivation in HTLV-mediated T-lymphocyte transformation.
- To investigate the distinct roles of CREB/ATF and NFkappaB/Rel signaling pathways in HTLV-2 Tax function.
- To correlate specific Tax-2 mutations with their impact on viral replication and cellular transformation.
Main Methods:
- Utilized a unique HTLV-2 provirus (HTLV(c-enh)) that replicates independently of Tax.
- Employed a panel of well-characterized tax-2 mutations.
- Assessed the ability of mutated viruses to transform primary human T lymphocytes.
Main Results:
- Viruses with tax-2 mutations abrogating NFkappaB/Rel or CREB/ATF activation showed distinct phenotypes.
- These mutated viruses failed to transform primary human T lymphocytes.
- NFkappaB/Rel activation appears critical for early proliferative signals in transformation.
Conclusions:
- NFkappaB/Rel activation is essential for early proliferation in T-lymphocyte transformation.
- CREB/ATF activation is required for the fully transformed state.
- Further research is needed to link Tax domains to specific functions like gene transcription and cell cycle control.