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A Human T-Cell Lymphotropic Virus Type 1 Enhancer of Myc Transforming Potential Stabilizes Myc-TIP60 Transcriptional Interactions

Soumya Awasthi,¹ Anima Sharma,¹ Kasuen Wong,¹ Junyu Zhang,¹ Elizabeth F. Matlock,¹ Lowery Rogers,¹ Pamela Motloch,¹ Shigeki Takemoto,² Hirokuni Taguchi,² Michael D. Cole,³ Bernhard Lüscher,⁴ Oliver Dittrich,^4, Hideaki Tagami,⁵ Yoshihiro Nakatani,⁵ Monnie McGee,⁶ Anne-Marie Girard,⁷ Luke Gaughan,⁸ Craig N. Robson,⁸ Raymond J. Monnat Jr.,⁹ and Robert Harrod^1*

Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, 334-DLS, 6501 Airline Drive, Dallas, Texas 75275-0376,¹ Department of Hematology and Respiratory Medicine, Kochi Medical School Hospital, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan,² Department of Pharmacology and Toxicology, Dartmouth University Medical School and the Norris Cotton Cancer Center, Hanover, New Hampshire 03755,³ Abt. Biochemie und Molekularbiologie, Institute für Biochemie, Klinikum der RWTH, Pauwelssttrasse 30, 52057 Aachen, Germany,⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115,⁵ Department of Statistical Science, Southern Methodist University, 3225 Daniels Avenue, Dallas, Texas 75275-0332,⁶ Center for Gene Research and Biotechnology, Oregon State University, Corvallis, Oregon 97331,⁷ School of Surgical Sciences, University of Newcastle upon Tyne Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom,⁸ Department of Pathology, University of Washington, Box 357705, Seattle, Washington 98195-7705⁹

Received 10 January 2005/ Returned for modification 17 February 2005/ Accepted 6 April 2005

The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4⁺ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30^II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30^II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30^II/Myc-TIP60 chromatin-remodeling complexes. The p30^II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30^II interact with the TIP60 HAT, and p30^II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30^II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.

Present address: Medizinische Hochschule Hannover, Institut für Pharmakologie, 30625 Hannover, Germany.

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