Cell cycle-dependent nuclear export of Cdh1p may contribute to the inactivation of APC/CCdh1
Cell cycle-dependent nuclear export of Cdh1p may contribute to the inactivation of APC/CCdh1
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DOI：
10.1093/emboj/cdf634
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发表时间：
2002-12-02
期刊：
影响因子：
11.4
通讯作者：
Peter, M
中科院分区：
文献类型：
--
作者：
Jaquenoud, M;van Drogen, F;Peter, M
CDH1p是后期促进复合体(APC/C)的底物特异性亚基，在细胞周期的G(1)期，它作为E3泛素连接酶降解有丝分裂周期蛋白Clb2p和其他底物。Cdh1p被磷酸化，因此在G(1)/S转变时主要由Cdc28P-Clb5p失活。我们发现，在细胞周期的G(1)期，CDH1p是有核的，但在S期和有丝分裂结束之间，它重新分布到细胞质中。CDH1p的核输出受磷酸化调控，需要有活性的CDc28p激酶。CDh1p与Importin Pse1p和Exportin Msn5p结合，这是在体内促进CDh1p有效输出的必要条件和充分条件。虽然msn5Delta细胞是活的，但它们对CDh1p的过度表达很敏感。同样，CDH1p的一种突变形式，它是有核的，当在野生型细胞中过度表达时，可以防止Clb2p的积累并导致细胞周期停滞。综上所述，这些结果表明，Msn5p依赖于磷酸化的CDh1p核输出有助于APC/C-CDh1的有效失活。
Cdh1p is a substrate-specific subunit of the anaphase-promoting complex (APC/C), which functions as an E3 ubiquitin ligase to degrade the mitotic cyclin Clb2p and other substrates during the G(1) phase of the cell cycle. Cdh1p is phosphorylated and thereby inactivated at the G(1)/S transition predominantly by Cdc28p-Clb5p. Here we show that Cdh1p is nuclear during the G(1) phase of the cell cycle, but redistributes to the cytoplasm between S phase and the end of mitosis. Nuclear export of Cdh1p is regulated by phosphorylation and requires active Cdc28p kinase. Cdh1p binds to the importin Pse1p and the exportin Msn5p, which is necessary and sufficient to promote efficient export of Cdh1p in vivo. Although msn5Delta cells are viable, they are sensitive to Cdh1p overexpression. Likewise, a mutant form of Cdh1p, which is consitutively nuclear, prevents accumulation of Clb2p and leads to cell cycle arrest when overexpressed in wild-type cells. Taken together, these results suggest that phosphorylation-dependent nuclear export of Cdh1p by Msn5p contributes to efficient inactivation of APC/C-Cdh1.