A mouse model for cyclin E-dependent genetic instability and tumorigenesis
A mouse model for cyclin E-dependent genetic instability and tumorigenesis
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DOI：
10.1016/j.ccr.2005.06.010
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发表时间：
2005-07-01
期刊：
影响因子：
50.3
通讯作者：
Roberts, JM
中科院分区：
文献类型：
--
作者：
Loeb, KR;Kostner, H;Roberts, JM
小鼠细胞周期蛋白E的泛素化是由苏氨酸393上的磷酸化触发的。细胞周期蛋白ET 393 A基因敲入小鼠表现出细胞周期蛋白E稳定性增加，但没有表型异常。重要的是，p53通路的缺失加剧了T393 A突变的影响。因此，在p21（-/-）细胞中，T393 A突变对细胞周期蛋白E丰度及其相关激酶活性具有夸大的影响，这导致异常的细胞周期进展，以及涉及染色体断裂和易位的遗传不稳定性。此外，cyclin ET 393 A与p53缺陷协同作用，加速cyclin ET 393 A p53（-/-）小鼠的肿瘤发生; Ras在体外更容易转化cyclin ET 393 A p53（-/-）细胞而不是p53（-/-）细胞; cyclin ET 393 A小鼠对Ras诱导的肺癌的易感性大大增加。
Ubiquitination of murine cyclin E is triggered by phosphorylation on threonine 393. Cyclin ET393A knockin mice exhibited increased cyclin E stability, but no phenotypic abnormalities. Importantly, loss of the p53 pathway exacerbated the effect of the T393A mutation. Thus, in p21(-/-) cells the T393A mutation had an exaggerated effect on cyclin E abundance and its associated kinase activity, which caused abnormal cell cycle progression, and genetic instability involving chromosome breaks and translocations. Moreover, cyclin ET393A acted synergistically with p53 deficiency to accelerate tumorigenesis in cyclin ET393A p53(-/-) mice; Ras more readily transformed cyclin ET393A p53(-/-) cells than p53(-/-) cells in vitro; and cyclin ET393A mice had a greatly increased susceptibility to Ras-induced lung cancer.