Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila discslarge tumor suppressor protein, hDLG, and perturbs its function in cell growth control

HTLV-1 Tax oncoprotein interacts with various cellular factors and modulate s transcription and the cell cycle. To identify more cellular targets, we e mployed the yeast two hybrid system with Tax using a human cDNA library, an d isolated a cDNA encoding the human counterpart of Drosophila discs large tumor suppressor protein, hDLG. Tax binding to hDLG was confirmed in vitro and also in HTLV-l-infected T-cells. Furthermore, hDLG was found to be effi ciently phosphorylated in Tax-transfected cells and HTLV-l-infected T-cells . The C-terminus of Tax and the PDZ domain of hDLG were responsible for the binding of Tax to hDLG. The C-terminal peptide of Tax prevented the bindin g of hDLG to APC tumor suppressor gene product, suggesting inhibition of hD LG function by Tax. Over-expression of hDLG in NIH3T3 cells by microinjecti on induced a reduction of BrdU incorporation into DNA, but coexpression of Tax suppressed this inhibitory effect of hDLG. These results suggest that h DLG arrested the cell cycle and that Tax canceled this inhibitory action of hDLG through targeting hDLG. Therefore, Tax affects this novel regulatory pathway of the cell cycle alteration, of which seems to play a role in the development of human cancer.