Antiapoptotic effect of human T-cell leukemia virus type 1 tax protein correlates with its creb transcriptional activity

Defects in the regulation of programmed cell death play a fundamental role in the development of neoplasia and neurological disorders, both of which are linked to the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection. We previously showed that the HTLV-1 Tax protein protects from apoptosis induced by serum starvation by preventing cytochrome c release and Bax relocation to mitochondria, two early events in the mitochondrial apoptotic pathway. As a natural extension of these findings, and to better define the action of Tax, in the present study, we investigated the outcome of Tax and two mutants which are inactive in CREB/ATF (M47) or NF-kappaB (M22) pathways, in the control of apoptosis induced by the proapoptotic Bax protein. We found that activation of CREB, rather than NF-kappaB, is a key phenomenon in preventing apoptosis. Furthermore, the importance of CREB activation is strengthened by experiments with CREB mutants, treatment with forskolin, and in situ analysis of P-CREB status in cells transfected with Tax or its nonprotecting M47 mutant. Considered together, these results underscore a primary role of CREB in preventing apoptosis triggered by Bax, and suggest that Tax might act by affecting the phosphorylation state of CREB.     

Mutational analysis of human T-cell leukemia virus type 2 Tax.

A mutational analysis of human T-cell leukemia virus type 2 (HTLV-2) Tax (Tax-2) was performed to identify regions within Tax-2 important for activation of promoters through the CREB/ATF or NF-kappaB/Rel signaling pathway. Tax-2 mutations within the putative zinc-binding region as well as mutations at the carboxy terminus disrupted CREB/ATF transactivation. A single mutation within the central proline-rich region of Tax-2 disrupted the transactivation of the NF-kappaB/Rel pathway. Surprisingly, this mutation, which is thought to be in a separate activation domain, was suppressed by mutations within or around the putative zinc-binding region, suggesting an interaction between these two regions. These analyses indicate that the functional regions or domains important for transactivation through the CREB/ATF or NF-kappaB/Rel signaling pathway are similar, but not identical, in Tax-1 and Tax-2. Identification of these distinct Tax-2 mutants should facilitate comparative biological studies of HTLV-1 and HTLV-2 and ultimately lead to the determination of the functional importance of Tax trans-acting capacities in T-lymphocyte transformation by HTLV.