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

Abstract

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 NFB/Rel transcriptional activation pathway to cellular transformation have yielded conflicting results. In this study, we use a unique HTLV-2 provirus (HTLV c-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 NFB/Rel signaling pathway. Our results demonstrate that viruses expressing tax-2 mutations that selectively abrogate NFB/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 NFB/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.

Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2

“…HTLVc-enh containing a mutant Tax that fails to activate NFkB is indistinguishable in phenotype from a Tax knockout virus. It appears that CREB/ATF activation by Tax is required to promote sustained cell growth and IL-2-independent cellular transformation (Ross et al, 2000).…”

Human T-Cell Leukemia Virus Type I at Age 25: A Progress Report

“…18,19]. Tax is also the HTLV-I-encoded cell transforming protein which serves to increase proliferation and clonal expansion of virus-infected cells (13,(20)(21)(22). In addition to Tax, the viral Rex protein (23), and other viral accessory proteins (24) also contribute to HTLV-I replication.…”

Activation of NF-κB by HTLV-I and implications for cell transformation

“…Tax induces cell immortalization and transformation in vitro (Grassmann et al, 1989;Pozzatti et al, 1990;Tanaka et al, 1990;Grassmann et al, 1992;Akagi and Shimotohno, 1993) as well as tumor formation in transgenic mice Nerenberg et al, 1987;Grossman et al, 1995). More recently, an essential role of Tax in the induction of T-cell immortalization by HTLV-I as well as a related virus, HTLV-II, has been demonstrated by a genetic approach (Robek and Ratner, 1999;Ross et al, 2000).…”