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Journal of Virology, March 2000, p. 2655-2662, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Human T-Cell Leukemia Virus Type 2 Tax Mutants That Selectively Abrogate NFkappa B or CREB/ATF Activation Fail To Transform Primary Human T Cells

Ted M. Ross,1,dagger Murli Narayan,2 Zhi-Yu Fang,1 Alex C. Minella,1 and Patrick L. Green2,3,4,*

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363,1 and Departments of Veterinary Biosciences2 and Molecular Virology, Immunology, and Medical Genetics3 and Center for Retrovirus Research and Comprehensive Cancer Center,4 The Ohio State University, Columbus, Ohio 43210-1093

Received 27 August 1999/Accepted 14 December 1999

Human T-cell leukemia virus (HTLV) Tax protein has been implicated in the HTLV oncogenic process, primarily due to its pleiotropic effects on cellular genes involved in growth regulation and cell cycle control. To date, several approaches attempting to correlate Tax activation of the CREB/activating transcription factor (ATF) or NFkappa B/Rel transcriptional activation pathway to cellular transformation have yielded conflicting results. In this study, we use a unique HTLV-2 provirus (HTLVc-enh) that replicates by a Tax-independent mechanism to directly assess the role of Tax transactivation in HTLV-mediated T-lymphocyte transformation. A panel of well-characterized tax-2 mutations is utilized to correlate the respective roles of the CREB/ATF or NFkappa B/Rel signaling pathway. Our results demonstrate that viruses expressing tax-2 mutations that selectively abrogate NFkappa B/Rel or CREB/ATF activation display distinct phenotypes but ultimately fail to transform primary human T lymphocytes. One conclusion consistent with our results is that the activation of NFkappa B/Rel provides a critical proliferative signal early in the cellular transformation process, whereas CREB/ATF activation is required to promote the fully transformed state. However, complete understanding will require correlation of Tax domains important in cellular transformation to those Tax domains important in the modulation of gene transcription, cell cycle control, induction of DNA damage, and other undefined activities.

* Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Rd., Columbus, OH 43210-1093. Phone: (614) 688-4899. Fax: (614) 292-6473. E-mail: green.466{at}osu.edu.

dagger Present address: Yerkes Primate Research Center, Emory University, Atlanta, GA 30329.

Journal of Virology, March 2000, p. 2655-2662, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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