Abstract
Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), which is an aggressive form of human T-cell malignancy. The viral protein, Tax, immortalizes human T-cells and inhibits various types of apoptosis, and is thought to play crucial roles in the development of ATL. We have recently demonstrated that Tax induces the constitutive expression of the anti-apoptotic protein, Bcl-xL, in a mouse T-cell line. The mouse, however, is not a natural host of HTLV-I, and HTLV-I does not induce this malignancy in mice. We thus examined whether Tax also activates the expression of Bcl-xL in human T-cells. Expression of Tax in a human T-cell line, Jurkat, induced the expression of the Bcl-xL gene, but did not significantly affect the expression of the other apoptosis-related genes, Bcl-2 and Bax. Transient transfection assays showed that Tax stimulated human Bcl-xL promoter activity in Jurkat cells. Deletion of the two potential nuclear factor (NF)-κ B binding sites in the human Bcl-xL promoter significantly decreased Tax-induced transactivation. In addition to NF-κB, Tax activates transcription through the c-AMP responsive element binding protein (CREB). Tax mutants segregating these two pathways showed that both the NF-κB and CREB pathways of Tax are required for maximum activation of a human Bcl-xL promoter, nevertheless, NF-κB alone was sufficient for that of a mouse Bcl-xL promoter. Northern blot analysis showed that all the human T-cell lines expressing Tax had higher levels of Bcl-xL mRNA than HTLV-I-uninfected ones. Furthermore, the sample from one patient with ATL expressed higher levels of Bcl-xL mRNA compared with levels from uninfected peripheral blood mononuclear cells. Our results suggest that Tax induces the expression of Bc-xL through the NF-κB and CREB pathways in HTLV-I-infected human T-cells, and then inhibits apoptosis, and such inhibition is necessary for the infected cells to advance to the leukemia in vivo.
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Mori, N., Fujii, M., Cheng, G. et al. Human T-cell Leukemia Virus Type I Tax Protein Induces the Expression of Anti-Apoptotic Gene Bcl-xL in Human T-Cells through Nuclear Factor-κB and c-AMP Responsive Element Binding Protein Pathways. Virus Genes 22, 279–287 (2001). https://doi.org/10.1023/A:1011158021749
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DOI: https://doi.org/10.1023/A:1011158021749