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Journal of Virology, November 2006, p. 10497-10505, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00739-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Human T-Cell Leukemia Virus Type 1 Tax Dysregulates ß-Catenin Signaling{triangledown}

Mariko Tomita,1 Akira Kikuchi,3 Tetsu Akiyama,4 Yuetsu Tanaka,2 and Naoki Mori1*

Division of Molecular Virology and Oncology, Graduate School of Medicine,1 Division of Immunology, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan,2 Department of Biochemistry, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan,3 Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan4

Received 11 April 2006/ Accepted 8 August 2006

Dysregulation of ß-catenin signaling has been implicated in the malignant transformation of cells. However, the role of ß-catenin in the human T-cell leukemia virus type 1 (HTLV-1)-induced transformation of T cells is unknown. Here we found that ß-catenin protein was overexpressed in the nucleus and that ß-catenin-dependent transcription was significantly enhanced in Tax-positive HTLV-1-infected T-cell lines compared to that in Tax-negative HTLV-1-infected T-cell lines. Transfection with ß-catenin-specific small interfering RNA inhibited the growth of the Tax-positive HTLV-1-infected T-cell line HUT-102. Transient transfection of Tax appeared to enhance ß-catenin-dependent transcription by stabilizing the ß-catenin protein via activation of the cyclic AMP (cAMP) response element-binding protein. HTLV-1-infected T-cell lines overexpressing ß-catenin also showed increased Akt activity via Tax activation of the cAMP response element-binding protein, resulting in the phosphorylation and inactivation of glycogen synthase kinase 3ß, which phosphorylates ß-catenin for ubiquitination. The phosphatidylinositol 3-kinase inhibitor LY294002 reduced ß-catenin expression in Tax-positive T-cell lines, and inactivation of glycogen synthase kinase 3ß by lithium chloride restored ß-catenin expression in Tax-negative T-cell lines. Finally, we showed that dominant-negative Akt inhibited Tax-induced ß-catenin-dependent transcription. These results indicate that Tax activates ß-catenin through the Akt signaling pathway. Our findings suggest that activation of ß-catenin by Tax may be important in the transformation of T cells by HTLV-1 infection.

* Corresponding author. Mailing address: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81 (98) 895-1130. Fax: 81 (98) 895-1410. E-mail: n-mori{at}med.u-ryukyu.ac.jp.

{triangledown} Published ahead of print on 18 August 2006.

Journal of Virology, November 2006, p. 10497-10505, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00739-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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