Degradation of cyclin A is regulated by acetylation.
Degradation of cyclin A is regulated by acetylation.
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DOI：
10.1038/onc.2009.127
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发表时间：
2009-07-23
期刊：
影响因子：
8
通讯作者：
Bachs, O.
中科院分区：
文献类型：
--
作者：
Mateo, F.;Vidal-Laliena, M.;Canela, N.;Busino, L.;Martinez-Balbas, M. A.;Pagano, M.;Agell, N.;Bachs, O.
细胞周期蛋白A在S期开始积累，在G2期和有丝分裂早期保持高水平，并在前中期降解。在这里，我们报道了乙酰转移酶P/CAF直接与细胞周期蛋白A相互作用，其结果是在赖氨酸54、68、95和112处被乙酰化。最大的乙酰化同时发生在有丝分裂的泛素化，表明乙酰化对细胞周期蛋白A的稳定性的重要性。这进一步证实了观察，假乙酰化的细胞周期蛋白A突变体可以被泛素化，而nonacetylatable突变体不能。不可乙酰化的突变体比细胞周期蛋白A WT（cycA WT）更稳定，并在有丝分裂时阻滞细胞周期。此外，在用组蛋白去乙酰化酶抑制剂处理的细胞中，细胞周期蛋白A乙酰化增加，其稳定性降低，从而支持乙酰化对细胞周期蛋白A降解的功能。虽然非乙酰化突变体不能被泛素化，但它与其降解所需的蛋白质（cdks，Cks，Cdc 20，Cdh 1和APC/C）相互作用。事实上，它与cdk的结合增加，并且它与这些激酶的复合物显示出比对照cycA WT-cdk复合物更高的活性。所有这些结果表明，细胞周期蛋白A乙酰化在特定的赖氨酸是至关重要的细胞周期蛋白A的稳定性，也有一个功能，在调节cycA-cdk活性。
Cyclin A accumulates at the onset of S phase, rem ains high during G2 and early mitosis and is degraded at prometaphase. Here, we report that the acetyltransferase P/CAF directly interacts with cyclin A that as a consequence becomes acetylated at lysines 54,68, 95 and 112. Maximal acetylation occurs simultaneously to ubiquitylation at mitosis, indicating importance of acetylation on cyclin A stability. This was further confirmed by the observation that the pseudoacetylated cyclin A mutant can be ubiquitylated whereas the nonacetylatable mutant cannot. The nonacetylatable mutant is more stable than cyclin A WT (cycA WT) and arrests cell cycle at mitosis. Moreover, in cells treated with histone deacetylase inhibitors cyclin A acetylation increases and its stability decreases, thus supporting the function of acetylation on cyclin A degradation. Although the nonacetylatable mutant cannot be ubiquitylated, it interacts with the proteins needed for its degradation (cdks, Cks, Cdc 20, Cdh1 and APC/C). In fact, it s association with cdks is increased and its complexes with these kinases display higher activity than control cycA WT–cdk complexes. All these results indicate that cyclin A acetylation at specific lysines is crucial for cyclin A stability and also has a function in the regulation of cycA-cdk activity.
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