HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 ONCOPROTEIN TAX TARGETS THE HUMAN MITOTIC CHECKPOINT PROTEIN MAD1

In searching for cellular targets of the HTLV-I oncoprotein Tax, we id entified TXBP181,which we characterized as the human homolog of yeast mitotic checkpoint MAD1 protein. Evidence supporting TXBP181 as HsMAD1 includes sequence conservation with yeast MAD1, hyperphosphorylation during S/G(2)/M phases and upon treatment of cells with nocodazole, an d binding to HsMAD2. HsMAD1 functions as a homodimer. It localizes to the centrosome during metaphase and to the spindle midzone and the mid body during anaphase and telophase. Expression of either Tax or a tran sdominant-negative TXBP181 results in multinucleated cells, a phenotyp e consistent with a loss of HsMAD1 function. We propose a model of vir al transformation in which Tax targets TXBP181, thereby abrogating a m itotic checkpoint.