Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence

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Abstract
The human T‐lymphotropic virus type 1 (HTLV‐1) Tax binds the anaphase promoting complex (APC) and activates it ahead of schedule. Here, we show that APC activation by Tax induces rapid senescence ( tax ‐IRS) independently of p53 and pRB. In response to tax , cyclin A, cyclin B1, securin, and Skp2 becomes polyubiquitinated and degraded starting in S phase. This is followed by a surge in p21 CIP1/WAF1 and p27 KIP1 in mid to late S and G2/M leading to a permanent G1 arrest. Tax‐positive HTLV‐1‐transformed T‐cell lines express elevated levels of p21 CIP1/WAF1 , but low levels of p27 KIP1 . Finally, Tax can be stably expressed in p27 KIP1 ‐null NIH3T3 cells. These results indicate that APC activation by Tax causes inactivation of SCFSkp2 and stabilization of p21 CIP1/WAF1 and p27 KIP1 . The build‐up of p21 CIP1/WAF1 and especially p27 KIP1 commits cells to senescence. Evading tax ‐IRS through a loss of p27 KIP1 function is likely to be critical for cell transformation by Tax and development of adult T‐cell leukemia after HTLV‐1 infection. Finally, activation of APC ahead of schedule may be exploited to arrest cancer cell growth.