Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line
Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line
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DOI：
10.1038/35095076
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发表时间：
2001-09-20
期刊：
影响因子：
64.8
通讯作者：
Reed, SI
中科院分区：
文献类型：
--
作者：
Strohmaier, H;Spruck, CH;Reed, SI
细胞周期蛋白E是细胞周期蛋白依赖性激酶CDK2的激活剂之一，在细胞周期G(1)-S相变附近表达，被认为是启动DNA复制和其他S期功能的关键因子(1-3)。细胞周期蛋白E在G(1)-S交界处的积累是通过周期性转录和与细胞周期蛋白E-4的自磷酸化相关的调节蛋白分解来实现的。Cyclin E表达的适当时机和幅度似乎很重要，因为Cyclin E水平的升高与多种恶性肿瘤有关(5，6)，而Cyclin E的结构性表达导致基因组不稳定(7)。在这里，我们证明了磷酸化的细胞周期蛋白E的周转依赖于一种SCF型蛋白-泛素连接酶，它包含酵母CDC4的人类同源物，后者是一种F-box蛋白，包含WD40的重复序列(一个单位包含大约40个残基，在定义的位置上有色氨酸(W)和天冬氨酸(D))。编码hCDC4的基因在一个乳腺癌细胞系中被发现发生了突变，该细胞系表达极高水平的细胞周期蛋白E。
Cyclin E, one of the activators of the cyclin-dependent kinase Cdk2, is expressed near the G(1)-S phase transition and is thought to be critical for the initiation of DNA replication and other S-phase functions(1-3). Accumulation of cyclin E at the G(1)-S boundary is achieved by periodic transcription coupled with regulated proteolysis linked to autophosphorylation of cyclin E-4. The proper timing and amplitude of cyclin E expression seem to be important, because elevated levels of cyclin E have been associated with a variety of malignancies(5,6) and constitutive expression of cyclin E leads to genomic instability(7). Here we show that turnover of phosphorylated cyclin E depends on an SCF-type protein-ubiquitin ligase that contains the human homologue of yeast Cdc4, which is an F-box protein containing repeated sequences of WD40 (a unit containing about 40 residues with tryptophan (W) and aspartic acid (D) at defined positions). The gene encoding hCdc4 was found to be mutated in a cell line derived from breast cancer that expressed extremely high levels of cyclin E.