Human T-cell leukemia virus type I Tax protein induces the expression of anti-apoptotic gene Bcl-x(L) in human T-cells through nuclear factor-kappa Band c-AMP responsive element binding protein pathways

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 maligna ncy. The viral protein, Tax, immortalizes human T-cells and inhibits variou s types of apoptosis, and is thought to play crucial roles in the developme nt of ATL. We have recently demonstrated that Tax induces the constitutive expression of the anti-apoptotic protein, Bcl-x(L), in a mouse T-cell line. The mouse, however, is not a natural host of HTLV-I, and HTLV-I does not i nduce this malignancy in mice. We thus examined whether Tax also activates the expression of Bcl-x(L) in human T-cells. Expression of Tax in a human T -cell line, Jurkat, induced the expression of the Bcl-x(L) gene, but did no t significantly affect the expression of the other apoptosis-related genes, Bcl-2 and Bax. Transient transfection assays showed that Tax stimulated hu man Bcl-x(L) promoter activity in Jurkat cells. Deletion of the two potenti al nuclear factor (NF)-kappaB binding sites in the human Bcl-x(L) promoter significantly decreased Tax-induced transactivation. In addition to NF-kapp aB, Tax activates transcription through the c-AMP responsive element bindin g protein (CREB). Tax mutants segregating these two pathways showed that bo th the NF-kappaB and CREB pathways of Tax are required for maximum activati on of a human Bcl-x(L) promoter, nevertheless, NF-kappaB alone was sufficie nt for that of a mouse Bcl-x(L) promoter. Northern blot analysis showed tha t all the human T-cell lines expressing Tax had higher levels of Bcl-x(L) m RNA than HTLV-I-uninfected ones. Furthermore, the sample from one patient w ith ATL expressed higher levels of Bcl-x(L) mRNA compared with levels from uninfected peripheral blood mononuclear cells. Our results suggest that Tax induces the expression of Bc-x(L) through the NF-kappaB and CREB pathways in HTLV-I-infected human T-cells, and then inhibits apoptosis, and such inh ibition is necessary for the infected cells to advance to the leukemia in v ivo.