Differential Transcriptional Activation by Human T-Cell Leukemia Virus Type 1 Tax Mutants Is Mediated by Distinct Interactions with CREB Binding Protein and p300

ABSTRACT

The human T-cell leukemia virus type 1 Tax protein transforms human T lymphocytes, which can lead to the development of adult T-cell leukemia. Tax transformation is related to its ability to activate gene expression via the ATF/CREB and the NF-κB pathways. Transcriptional activation of these pathways is mediated by the actions of the related coactivators CREB binding protein (CBP) and p300. In this study, immunocytochemistry and confocal microscopy were used to localize CBP and p300 in cells expressing wild-type Tax or Tax mutants that are able to selectively activate gene expression from either the NF-κB or ATF/CREB pathway. Wild-type Tax colocalized with both CBP and p300 in nuclear bodies which also contained ATF-1 and the RelA subunit of NF-κB. However, a Tax mutant that selectively activates gene expression from only the ATF/CREB pathway colocalized with CBP but not p300, while a Tax mutant that selectively activates gene expression from only the NF-κB pathway colocalized with p300 but not CBP. In vitro and in vivo protein interaction studies indicated that the integrity of two independent domains of Tax delineated by these mutants was involved in the direct interaction of Tax with either CBP or p300. These studies are consistent with a model in which activation of either the NF-κB or the ATF/CREB pathway by specific Tax mutants is mediated by distinct interactions with related coactivator proteins.

ACKNOWLEDGMENTS

We thank Richard Goodman for providing the CBP clone, David Livingston for providing p300 cDNA and the p300 monoclonal antibody, Joan Steitz and Gunther Schutz for providing the Sm and CREM antibodies, and the NIH AIDS Research and Reagent Program for providing the MT2 cells and the Tax monoclonal antibody. In addition, we acknowledge Caroline Vanhulle for technical assistance and Sharon Johnson and Anthony Cancel for the preparation of the manuscript and the figures.

This work was supported by grants from the Belgian Fonds National de la Recherche Scientifique and Télévie, from the Fonds de Financement de la Recherche Cancérologique de la CGER Assurances, from the NIH, and from the Council of Tobacco Research.