Chk1激酶通过与14-3-3结合负向调节Cdc25A磷酸酶的有丝分裂功能。
Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding.
作者信息
Chen Mei-Shya, Ryan Christine E, Piwnica-Worms Helen
机构信息
Howard Hughes Medical Institute, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.
出版信息
Mol Cell Biol. 2003 Nov;23(21):7488-97. doi: 10.1128/MCB.23.21.7488-7497.2003.
Abstract
The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. Mutation of T507 to alanine (T507A) enhanced the biological activity of Cdc25A. Cdc25A(T507A) was more efficient in binding to cyclin B1, activating cyclin B1-Cdk1, and promoting premature entry into mitosis. We propose that the Chk1/Cdc25A/14-3-3 pathway functions to prevent cells from entering into mitosis prior to replicating their genomes to ensure the fidelity of the cell division process.
摘要
哺乳动物细胞周期事件的顺序和保真度与Chk1激酶-Cdc25A磷酸酶途径的完整性密切相关。Chk1磷酸化作用使Cdc25A靶向降解，并且如本文所示，抑制Cdc25A与其有丝分裂底物细胞周期蛋白B1-Cdk1之间的相互作用。Cdc25A丝氨酸178和苏氨酸507位点的磷酸化促进14-3-3结合，并且Chk1在体外使这两个位点磷酸化。将苏氨酸507突变为丙氨酸（T507A）增强了Cdc25A的生物学活性。Cdc25A（T507A）在结合细胞周期蛋白B1、激活细胞周期蛋白B1-Cdk1以及促进过早进入有丝分裂方面更有效。我们提出，Chk1/Cdc25A/14-3-3途径的作用是防止细胞在基因组复制之前进入有丝分裂，以确保细胞分裂过程的保真度。
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