Genetic Dissection of Mammalian Cdc7 Kinase: Cell Cycle and Developmental Roles
Genetic Dissection of Mammalian Cdc7 Kinase: Cell Cycle and Developmental Roles
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DOI：
10.4161/cc.3.3.730
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发表时间：
2004-03
期刊：
影响因子：
4.3
通讯作者：
Jung Min Kim;H. Masai
中科院分区：
文献类型：
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作者：
Jung Min Kim;H. Masai
Cdc7 最初由 Hartwell1 发现，是一种出芽酵母突变体，在 S 期开始前立即停止，在进化过程中是保守的，在有丝分裂 DNA 复制的启动中发挥重要作用。小鼠胚胎干细胞中 Cdc7 的诱导失活导致 DNA 合成快速停止，随后激活检查点反应，导致 p53 激活并最终导致 p53 介导的细胞凋亡。这表明哺乳动物基因组的持续复制需要 Cdc7 激酶，并且 Cdc7 激酶的丢失可能会产生停滞的复制叉信号。表达低水平转基因编码的 Cdc7 蛋白的 Cdc7-/- 小鼠或胚胎成纤维细胞 (MEF) 是可行的，但表现出体型减小、生殖细胞发育受损和细胞增殖减少。有趣的是，这些表型在很大程度上通过额外的转基因拷贝的存在得到纠正，从而导致 Cdc7 表达水平增加。这表明正常细胞增殖和特定器官发育需要临界水平的 Cdc7。来自哺乳动物的这些结果将与在酵母中观察到的 Cdc7 突变的多效性效应一起讨论。
Cdc7, originally discovered by Hartwell1 as a budding yeast mutant that arrests immediately before the onset of S phase, is conserved through evolution and plays essential roles in initiation of mitotic DNA replication. Inducible inactivation of Cdc7 in mouse embryonic stem cells leads to rapid cessation of DNA synthesis and the subsequent activation of checkpoint responses, resulting in p53 activation and eventually p53-mediated apoptosis. This indicates a requirement of Cdc7 kinase for ongoing replication of mammalian genomes, and loss of Cdc7 kinase presumably generates arrested replication fork signals. Cdc7-/- mice or embryonic fibroblast cells (MEFs) expressing a low level of transgene-encoded Cdc7 protein are viable but exhibit reduced body size with impaired germ cell development and decreased cell proliferation. Interestingly, these phenotypes are largely corrected by the presence of an additional copy of the transgene, resulting in increased level of Cdc7 expression. This indicates the requirement of a critical level of Cdc7 for normal cell proliferation and development of specific organs. These results from mammals will be discussed in conjunction with the pleiotropic effects of Cdc7 mutation observed in yeasts.