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Journal of Virology, November 2007, p. 11900-11907, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00532-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cooperation of NF-B2/p100 Activation and the PDZ Domain Binding Motif Signal in Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax1 but Not HTLV-2 Tax2 Is Crucial for Interleukin-2-Independent Growth Transformation of a T-Cell Line

Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata 951-8510, Japan,¹ Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan,² Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France,³ Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan⁴

Received 11 March 2007/ Accepted 13 August 2007

Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-B2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-B2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-B2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-B2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1-specific functions play crucial roles in HTLV-1 leukemogenesis.

Published ahead of print on 22 August 2007.