Kuo Yu-Liang, Giam Chou-Zen
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
EMBO J. 2006 Apr 19;25(8):1741-52. doi: 10.1038/sj.emboj.7601054. Epub 2006 Apr 6.
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 SCF(Skp2) 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.
人类嗜T淋巴细胞病毒1型（HTLV-1）的Tax蛋白可结合后期促进复合物（APC）并使其提前激活。在此，我们发现Tax介导的APC激活可独立于p53和pRB诱导细胞快速衰老（tax-IRS）。在tax的作用下，细胞周期蛋白A、细胞周期蛋白B1、分离酶和Skp2从S期开始发生多聚泛素化并降解。随后，在S期中期至后期以及G2/M期，p21（CIP1/WAF1）和p27（KIP1）激增，导致细胞永久性停滞在G1期。Tax阳性的HTLV-1转化T细胞系中p21（CIP1/WAF1）表达水平升高，但p27（KIP1）表达水平较低。最后，Tax可在p27（KIP1）基因缺失的NIH3T3细胞中稳定表达。这些结果表明，Tax介导的APC激活导致SCF（Skp2）失活以及p21（CIP1/WAF1）和p27（KIP1）稳定。p21（CIP1/WAF1）尤其是p27（KIP1）的积累促使细胞进入衰老状态。通过丧失p27（KIP1）功能来逃避tax-IRS可能对Tax介导的细胞转化以及HTLV-1感染后成人T细胞白血病的发生至关重要。最后，提前激活APC可能被用于阻止癌细胞生长。
