DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase.
DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase.
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DEC1通过稳定细胞周期蛋白E蛋白调节乳腺癌细胞增殖并延缓细胞周期S期的进展
DOI：
10.1038/cddis.2015.247
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发表时间：
2015-09-24
影响因子：
9
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Bi H;Li S;Qu X;Wang M;Bai X;Xu Z;Ao X;Jia Z;Jiang X;Yang Y;Wu H
伴有高水平细胞周期蛋白E表达的乳腺癌通常表现出不良的预后和临床结果。已知有几种因子在细胞周期进程中调节细胞周期蛋白E的水平。转录因子DEC 1（也称为STRA 13和SHARP 2）在细胞增殖和凋亡中起重要作用。然而，其在细胞增殖中的作用机制知之甚少。在这项研究中，使用乳腺癌细胞系MCF-7和T47 D，我们表明，DEC 1可以抑制乳腺癌细胞的细胞周期进程独立于其转录活性。DEC 1过表达的时间依赖于细胞周期，可通过调节cyclin E蛋白水平影响细胞周期进程。DEC 1通过与细胞周期蛋白E相互作用在蛋白质水平上稳定细胞周期蛋白E。DEC 1的过表达抑制了cyclin E与其E3连接酶Fbw 7 α的相互作用，从而降低了多未泛素化cyclin E的水平，增加了非泛素化cyclin E的积累。此外，DEC 1还能促进Cdk 2在细胞核内的聚集和cyclin E/Cdk 2复合物的形成，并上调cyclin E/Cdk 2复合物的活性，从而抑制cyclin A与Cdk 2的结合。这具有延长S期和抑制小鼠异种移植模型中乳腺癌生长的作用。这些事件可能构成了DEC 1调节细胞增殖的基本步骤，从而开辟了基于蛋白质的分子策略消除表现出高水平表达细胞周期蛋白E的癌细胞的可能性。
Breast cancer that is accompanied by a high level of cyclin E expression usually exhibits poor prognosis and clinical outcome. Several factors are known to regulate the level of cyclin E during the cell cycle progression. The transcription factor DEC1 (also known as STRA13 and SHARP2) plays an important role in cell proliferation and apoptosis. Nevertheless, the mechanism of its role in cell proliferation is poorly understood. In this study, using the breast cancer cell lines MCF-7 and T47D, we showed that DEC1 could inhibit the cell cycle progression of breast cancer cells independently of its transcriptional activity. The cell cycle-dependent timing of DEC1 overexpression could affect the progression of the cell cycle through regulating the level of cyclin E protein. DEC1 stabilized cyclin E at the protein level by interacting with cyclin E. Overexpression of DEC1 repressed the interaction between cyclin E and its E3 ligase Fbw7α, consequently reducing the level of polyunbiquitinated cyclin E and increased the accumulation of non-ubiquitinated cyclin E. Furthermore, DEC1 also promoted the nuclear accumulation of Cdk2 and the formation of cyclin E/Cdk2 complex, as well as upregulating the activity of the cyclin E/Cdk2 complex, which inhibited the subsequent association of cyclin A with Cdk2. This had the effect of prolonging the S phase and suppressing the growth of breast cancers in a mouse xenograft model. These events probably constitute the essential steps in DEC1-regulated cell proliferation, thus opening up the possibility of a protein-based molecular strategy for eliminating cancer cells that manifest a high-level expression of cyclin E.