Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence
Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence
复制标题
DOI：
10.1038/sj.emboj.7601054
复制
发表时间：
2006-04-19
期刊：
影响因子：
11.4
通讯作者：
Giam, Chou-Zen
中科院分区：
文献类型：
--
作者：
Kuo, Yu-Liang;Giam, Chou-Zen
人类嗜T淋巴细胞病毒1型（HTLV-1）Tax结合后期促进复合物（APC）并提前激活它。在这里，我们表明，APC激活税收诱导快速衰老（税收IRS）独立的p53和pRB。作为对tax的响应，细胞周期蛋白A、细胞周期蛋白B1、securin和Skp 2从S期开始被多聚泛素化并降解。随后在S中期至晚期和G（2）/M中p21（CIP 1/WAF 1）和p27（KIP 1）激增，导致永久性G（1）停滞。Tax阳性HTLV-1转化的T细胞系表达升高水平的p21（CIP 1/WAF 1），但表达低水平的p27（KIP 1）。Tax在p27（KIP 1）缺失的NIH 3 T3细胞中稳定表达。这些结果表明Tax激活APC导致SCFSkp 2失活以及p21（CIP 1/WAF 1）和p27（KIP 1）稳定。p21（CIP 1/WAF 1），特别是p27（KIP 1）的积累使细胞衰老。通过p27（KIP 1）功能的丧失来逃避Tax-IRS可能对Tax引起的细胞转化和HTLV-1感染后成人T细胞白血病的发展至关重要。最后，提前激活APC可用于阻止癌细胞生长。
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 G(2)/M leading to a permanent G(1) 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.