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The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription

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.

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Acknowledgements

We thank Drs R Pestell (Thomas Jefferson University, Philadelphia, PA, USA) and A Baldwin (University of North Carolina, Chapel Hill, NC, USA) for the cyclin D1 luciferase constructs, and DY Jin (University of Hong Kong, Pokfulam, Hong Kong) for the TORC expression plasmids. We also thank Sarah Horstmann for helping with TORC2 cloning and expression and Holli Giebler for critical reading of the manuscript. This work was supported by a grant from the National Institutes of Health (CA055035).

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Correspondence to J K Nyborg.

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Kim, YM., Geiger, T., Egan, D. et al. The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription. Oncogene 29, 2142–2152 (2010). https://doi.org/10.1038/onc.2009.498

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  • DOI: https://doi.org/10.1038/onc.2009.498

Keywords

  • CRE
  • cell cycle
  • transducer of regulated CREB
  • CREB-regulated transcription co-activator
  • CRTC

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