Listovsky Tamar, Oren Yifat S, Yudkovsky Yana, Mahbubani Hiro M, Weiss Aryeh M, Lebendiker Mario, Brandeis Michael
Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
EMBO J. 2004 Apr 7;23(7):1619-26. doi: 10.1038/sj.emboj.7600149. Epub 2004 Mar 18.
The Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase mediates degradation of cell cycle proteins during mitosis and G1. Cdc20/Fzy and Cdh1/Fzr are substrate-specific APC/C activators. The level of mammalian Cdh1 is high in mitosis, but it is inactive and does not bind the APC/C. We show that when Cdh1 is active in G1 and G0, its levels are considerably lower and almost all of it is APC/C associated. We demonstrate that Cdh1 is subject to APC/C-specific degradation in G1 and G0, and that this degradation depends upon two RXXL-type destruction boxes. We further demonstrate that addition of Cdh1 to Xenopus interphase extracts, which have an inactive APC/C, activates it to degrade Cdh1. These observations indicate that Cdh1 mediates its own degradation by activating the APC/C to degrade itself. Elevated levels of Cdh1 are deleterious for cell cycle progression in various organisms. This auto-regulation of Cdh1 could thus play a role in ensuring that the level of Cdh1 is reduced during G1 and G0, allowing it to be switched off at the correct time.
后期促进复合物/细胞周期体（APC/C）泛素连接酶在有丝分裂和G1期介导细胞周期蛋白的降解。Cdc20/Fzy和Cdh1/Fzr是底物特异性的APC/C激活剂。哺乳动物Cdh1在有丝分裂期水平较高，但处于无活性状态，不与APC/C结合。我们发现，当Cdh1在G1期和G0期具有活性时，其水平显著降低，且几乎所有Cdh1都与APC/C相关联。我们证明，Cdh1在G1期和G0期会被APC/C特异性降解，且这种降解依赖于两个RXXL型破坏框。我们进一步证明，将Cdh1添加到无活性APC/C的非洲爪蟾间期提取物中，可激活提取物使其降解Cdh1。这些观察结果表明，Cdh1通过激活APC/C来降解自身，从而介导自身的降解。在各种生物体中，Cdh1水平升高对细胞周期进程有害。因此，Cdh1的这种自我调节可能在确保G1期和G0期Cdh1水平降低，使其在正确时间关闭方面发挥作用。
