HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule

摘要

Expression of the human T lymphotropic virus type I (HTLV-I) transactivator/oncoprotein, Tax, leads to faulty mitosis as reflected by chromosome aneuploidy, cytokinesis failure, and formation of micro- and multinucleated cells. Here we show that HTLV-I-transformed T cells progress through S/G2/M phases of the cell cycle with a delay. This delay is correlated with a decrease in the levels of cyclin A, cyclin B1, and securin. In tax-expressing cells, the Cdc20-associated anaphase promoting complex (APC^Cdc20), an E3 ubiquitin ligase that controls metaphase to anaphase transition, becomes active before cellular entry into mitosis as evidenced by premature cyclin B1 polyubiquitination and degradation during S/G2. Consistent with the notion that Tax activates APC^Cdc20 directly, Tax is found to coimmunoprecipitate with Cdc20 and Cdc27/APC3. The APC^Cdc20 activity prematurely activated by Tax remains sensitive to spindle checkpoint inhibition. Unscheduled activation of APC^Cdc20 by Tax provides an explanation for the mitotic abnormalities in HTLV-I-infected cells and is likely to play an important role in the development of adult T cell leukemia.