The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription
Open Access
- 25 January 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (14), 2142-2152
- https://doi.org/10.1038/onc.2009.498
Abstract
Adult T-cell leukemia/lymphoma is a fatal malignancy etiologically linked to infection with the human T-cell leukemia virus (HTLV-1). The virally encoded oncoprotein Tax activates the transcription of HTLV-1 and cellular genes by cooperating with cellular transcription factors. Cyclin D1 is a pivotal regulator of cell cycle progression, and increased expression strongly correlates with malignant transformation. Here, we characterize the mechanism of Tax transactivation of cyclin D1. We find that cyclin D1 transcript levels are elevated in HTLV-1 infected cells and that Tax physically associates with the cyclin D1 gene in vivo. Tax binds the cyclin D1 promoter-proximal cyclic AMP response element (CRE) in the presence of phosphorylated CREB (pCREB) in vitro, and together the Tax–pCREB complex recruits the cellular co-activator p300 to the promoter through this unconventional Tax-responsive element. We further show that the transducer of regulated CREB 2 (TORC2) cooperates with Tax to further enhance p300 recruitment to the cyclin D1 promoter in vitro. Tax and TORC2 in combination stimulate cyclin D1 expression in vivo, demonstrating the functional outcome of the binding interactions. Together, our findings support a model in which Tax-induced accumulation of cyclin D1 shortens the G1 phase of the cell cycle, promotes mitotic replication of the virus, and drives selection and expansion of malignant T-cells.This publication has 56 references indexed in Scilit:
- ChIP-seq accurately predicts tissue-specific activity of enhancersNature, 2009
- Regulation of Cyclin D1 and Wnt10b Gene Expression by cAMP-responsive Element-binding Protein during Early Adipogenesis Involves Differential Promoter MethylationOnline Journal of Public Health Informatics, 2008
- Cross Talk between Expression of the Human T-Cell Leukemia Virus Type 1 Tax Transactivator and the Oncogenic bHLH Transcription Factor TAL1Journal of Virology, 2008
- The coactivators CBP/p300 and the histone chaperone NAP1 promote transcription-independent nucleosome eviction at the HTLV-1 promoterProceedings of the National Academy of Sciences of the United States of America, 2008
- Human T-cell Leukemia Virus Type 1 Oncoprotein Tax Represses ZNF268 Expression through the cAMP-responsive Element-binding Protein/Activating Transcription Factor PathwayOnline Journal of Public Health Informatics, 2008
- The Human T-Cell Leukemia Virus Type 1 Tax Protein Confers CBP/p300 Recruitment and Transcriptional Activation Properties to Phosphorylated CREBMolecular and Cellular Biology, 2008
- Purification of CREB to apparent homogeneity: Removal of truncation products and contaminating nucleic acidProtein Expression and Purification, 2007
- Molecular Characterization of HTLV-1 Tax Interaction with the KIX Domain of CBP/p300Journal of Molecular Biology, 2007
- Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genomeNature Genetics, 2007
- TORC1 and TORC2 Coactivators Are Required for Tax Activation of the Human T-Cell Leukemia Virus Type 1 Long Terminal RepeatsJournal of Virology, 2006