PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line

Abstract

While human T-cell leukemia virus type 1 (HTLV-1) is associated with the development of adult T-cell leukemia (ATL), HTLV-2 has not been reported to be associated with such malignant leukemias. HTLV-1 Tax1 oncoprotein transforms a rat fibroblast cell line (Rat-1) to form multiple large colonies in soft agar, and this activity is much greater than that of HTLV-2 Tax2. We have demonstrated here that the increased number of transformed colonies induced by Tax1 relative to Tax2 was mediated by a PDZ domain-binding motif (PBM) in Tax1, which is absent in Tax2. Tax1 PBM mediated the interaction of Tax1 with the discs large (Dlg) tumor suppressor containing PDZ domains, and the interaction correlated well with the transforming activities of Tax1 and the mutants. Through this interaction, Tax1 altered the subcellular localization of Dlg from the detergent-soluble to the detergent-insoluble fraction in a fibroblast cell line as well as in HTLV-1-infected T-cell lines. These results suggest that the interaction of Tax1 with PDZ domain protein(s) is critically involved in the transforming activity of Tax1, the activity of which may be a crucial factor in malignant transformation of HTLV-1-infected cells in vivo.

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

“…This domain has been shown to be essential for CBP/p300 binding (Scoggin et al, 2001). Finally, and as in Tax1 but not in Tax2 (Rousset et al, 1998;Hirata et al, 2004), a putative class I PDZ-binding domain (Nourry et al, 2003) is present in all the simian Tax3 sequences that are available for analysis.…”

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

“…It was demonstrated further that deletion of only the PBM from Tax-1 led to reduced transformation activity in rat fibroblasts (Hirata et al, 2004). Transduction of Tax221 into HPCs results in suppression of hematopoiesis in vitro and induction of p21 cip1/waf1 and p27 kip1 expression.…”

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…Comparing HTLV-1 and HTLV-2 Tax proteins revealed that the reduced ability of Tax2 to transform cells correlated with a loss of the PBM in its C-terminus Endo et al, 2002). Tax1's interaction with hDLG correlates with its ability to induce colony formation in rat fibroblasts, suggesting a relevant role of this interplay in cellular transformation (Suzuki et al, 1999b;Hirata et al, 2004). A more extensive discussion of the PDZ-binding properties of Tax is found in an accompanying article in this issue (Hall and Fujii, this issue).…”