Transrepression of lck gene expression by human T-cell leukemia virus type 1-encoded p40tax

To understand the mechanism of p56lck protein downregulation observed in human T cells infected by human T-cell leukemia virus type 1 (HTLV-1), we have investigated the ability of the 3' end of the HTLV-1 genome as well as that of the tax and rex genes to modulate p56lck protein expression and p56lck mRNA synthesis. By using Jurkat T cells stably transfected with constructs that expressed either the 3' end of the HTLV-1 genome (JK C11-pMTEX), the tax gene (JK52-Tax) or the rex gene (JK9-Rex), we found that the expression of p40tax (Tax) was sufficient to modulate p56lck protein expression. Similarly, we found that the expression of the mRNA which encoded p56lck was repressed in Jurkat T cells which expressed Tax. This downregulation was shown to be proportional to the amount of tax mRNA found in the transfected cells, as evidenced by experiments that used cells (JPX-9) stably transfected with a tax gene driven by a cadmium-inducible promoter. Furthermore, cadmium induction of Tax in JPX-9 cells transiently transfected with a construct containing the chloramphenicol acetyltransferase (CAT) gene under control of the lck distal promoter (lck DP-CAT) resulted in the downregulation of CAT gene expression. In contrast, cadmium induction of Tax in JPX-9 cells transiently transfected with a CAT construct driven by a lck DP with a deletion extending from position -259 to -253 (a sequence corresponding to a putative E-Box) did not modulate CAT gene expression, suggesting that the effect of Tax on p56lck is mediated through an E-Box binding protein.     

Cytokine expression and tumorigenicity of large granular lymphocytic leukemia cells from mice transgenic for the tax gene of human T-cell leukemia virus type I

The human T-cell leukemia virus type I (HTLV-I) regulatory protein, Tax, has been speculated to play a major role in HTLV-I leukemogenesis. Indeed, several studies have suggested that upregulation of various cellular oncogenes and cytokines by Tax may explain the pathogenesis observed in HTLV-I-infected individuals, as well as several Tax-transgenic animal models. We report here the analysis of cytokine expression in a Tax-transgenic animal model with large granular lymphocytic (LGL) leukemia. Two different transgenic mice showed identical expression of interleukin-1alpha (IL-1alpha), IL-1beta, interferon gamma (IFNgamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in peripheral tail tumors. Interestingly, LGL cell lines derived from these same tumors expressed high levels of both IFNgamma and GM-CSF, which correlated with the level of Tax expression. These same LGL cell lines also expressed high levels of lymphocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1). Engraftment of these LGL cell lines into severe combined immunodeficient (SCID) mice led to the development of leukemia and lymphomas. Examination of these SCID mice showed that their pathology was nearly identical to that observed in the original Tax-transgenic mouse model. Both the Tax-transgenic and engrafted SCID mouse models allow for the analysis of cellular events that are required for tumor development associated with HTLV infection and suggest that Tax expression may be responsible for the upregulation of certain cytokines and adhesion molecules that affect the infiltrating capabilities of HTLV-I-infected cells.