The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein
The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein
复制标题
DOI：
10.1074/jbc.m205919200
复制
发表时间：
2002-10-18
影响因子：
4.8
通讯作者：
Möröy, T
中科院分区：
文献类型：
--
作者：
Geisen, C;Möröy, T
我们之前已经表明，周期蛋白E可以与组成活性Ha-Ras合作，恶性转化原代大鼠胚胎成纤维细胞。此外，我们证明了高水平的cyclin E表达增强了甲基亚硝基脲诱导的小鼠t细胞淋巴瘤的发展。为了进一步研究细胞周期蛋白E介导恶性转化的机制，我们对细胞周期蛋白E的功能进行了突变分析。在这里，我们发现细胞周期蛋白E突变体不能与Cdk2形成活性激酶复合物，不能将细胞从G期驱动到S期，但仍然可以与Ha-Ras合作恶性转化大鼠胚胎成纤维细胞。此外，Cdk2激活并不是细胞周期蛋白E挽救酵母三重cln突变能力的先决条件。我们还发现，细胞周期蛋白E的致癌特性并不完全符合其与负细胞周期调节因子p27（Kip1）或口袋蛋白p130相互作用的能力。这些发现表明，细胞周期蛋白E的致癌活性并不完全依赖于它作为G进展的正调节因子的能力。相反，我们提出cyclin E具有其他功能，独立于Cdk2激活和P27（Kip1）结合，这对其致癌活性有重要贡献。
We have previously shown that cyclin E can malignantly transform primary rat embryo fibroblasts in cooperation with constitutively active Ha-Ras. In addition, we demonstrated that high level cyclin E expression potentiates the development of methyl-nitroso-urea-induced T-cell lymphomas in mice. To further investigate the mechanism underlying cyclin E-mediated malignant transformation, we have performed a mutational analysis of cyclin E function. Here we show that cyclin E mutants defective to form an active kinase complex with Cdk2 are unable to drive cells from G, into S phase but can still malignantly transform rat embryo fibroblasts in cooperation with Ha-Ras. In addition, Cdk2 activation is not a prerequisite for the ability of cyclin E to rescue yeast triple cln mutations. We also find that the oncogenic properties of cyclin E did not entirely correspond with its ability to interact with the negative cell cycle regulator p27(Kip1) or the pocket protein p130. These findings suggest that the oncogenic activity of cyclin E does not exclusively rely on its ability as a positive regulator of G, progression. Rather, we propose that cyclin E harbors other functions, independent of Cdk2 activation and P27(Kip1) binding, that contribute significantly to its oncogenic activity.