The tat Gene of Human T-Lymphotropic Virus Type 1 Induces Mesenchymal Tumors in Transgenic Mice

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a suspected causative agent of adult T-cell leukemia. One of the viral genes encodes a protein (tat) that not only results in transactivation of viral gene expression but may also regulate the expression of certain cellular genes that are important for cell growth. Transgenic mice that expressed the authentic tat protein under the control of the HTLV-1 long terminal repeat were generated, and cell types that are permissive for the viral promoter and the effects of the tat gene on these cells were studied. Three of eight founder mice with high levels of expression of the transgene in muscle were bred and then analyzed. All developed soft tissue tumors at multiple sites between 13 to 17 weeks of age. This phenotype was transmitted to nine of nine offspring that inherited the tat gene and were available for analysis. The remaining five founders expressed the transgene in the thymus, as well as in muscle. This second group of mice all exhibited extensive thymic depletion and growth retardation; in all of these mice, death occurred between 3 to 6 weeks of age before tumors became macroscopically visible. The tat gene under the control of the HTLV-1 regulatory region showed tissue-specific expression and the tat protein efficiently induced mesenchymal tumors. The data establish tat as an oncogenic protein and HTLV-1 as a transforming virus.

The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins

“…Another interesting facet of Tax is its ability to transform cells. The oncogenic properties of this protein have been established by various assays, including transformation of primary T lymphocytes (Grassmann et al, 1989), cooperation with Ras in transformation of ®broblasts (Pozzatti et al, 1990) and induction of tumours in transgenic mice (Nerenberg et al, 1987;Benvenisty et al, 1992;Grossman et al, 1995). Tax transgenic mice are also known to develop several pathologies including thymus atrophy (Furuta et al, 1989), muscle degeneracy (Nerenberg and Wiley, 1989), arthritis (Iwakura et al, 1991) and a proliferation of ductal cells of the salivary gland resembling the SjoÈ gren syndrome (Green et al, 1989).…”

Transcriptional activation of survivin through the NF‐κB pathway by human T‐cell leukemia virus type I tax

“…Tax expression is sufficient to immortalize primary human CD4-positive T cells and transform rat fibroblast cell lines in vitro, 4,5 and is capable of inducing tumors in transgenic mice. 6 However, the exact mechanisms through which Tax exerts its oncogenic effects are not fully understood. Tax was originally identified as a transcriptional activator of the HTLV-I promoter in LTR, 7 but subsequent studies identified numerous other activities, including modulation of the expression of several cellular genes involved in cellular proliferation, such as genes for growth factors, growth factor receptors, cytoplasmic signal transmitters and nuclear transcription factors.…”

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

“…24 Tax also transforms rodent fibroblast cell lines and induces tumors in its transgenic mice. 25,26 Through all of these activities, Tax acts as a powerful oncogene and represents a very attractive viral protein for targeted therapy. However, among the wideranging properties of Tax oncoprotein, activation of the NF-kB pathway plays a crucial role in the proliferation and transformation of the infected cells, and hence also represents a critical therapeutic target.…”