Somatic cell type specific gene transfer reveals a tumor-promoting function for p21(Waf1/Cip1).
Somatic cell type specific gene transfer reveals a tumor-promoting function for p21(Waf1/Cip1).
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DOI：
10.1038/sj.emboj.7601886
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发表时间：
2007-11-14
期刊：
影响因子：
11.4
通讯作者：
Koff, Andrew
中科院分区：
文献类型：
--
作者：
Liu, Yuhui;Yeh, Nancy;Zhu, Xin-Hua;Leversha, Margaret;Cordon-Cardo, Carlos;Ghossein, Ronald;Singh, Bhuvanesh;Holland, Eric;Koff, Andrew
蛋白质如何参与肿瘤发生可能被其多功能性质所掩盖。例如，取决于细胞环境，cdk抑制剂可以影响细胞增殖、细胞运动性、细胞凋亡、受体酪氨酸激酶信号传导和转录。因此，为了确定蛋白质如何促进肿瘤发生，我们需要评估肿瘤发展所需的功能。在这里，我们证明了RCAS/TvA系统，最初开发引入癌基因到小鼠的体细胞，可以适应，使我们能够定义的贡献，不同的功能域使肿瘤的发展。研究生长因子诱导的少突胶质细胞瘤的发展，我们确定了Cy元件在p21中的关键作用，我们发现，细胞周期蛋白D1 T286 A，它积累在p21缺陷细胞的细胞核中，并结合cdk 4，可以绕过肿瘤发展过程中对p21的要求。这些遗传结果表明，p21通过细胞周期蛋白D1-cdk 4复合物发挥作用以支持肿瘤生长，并建立了使用体细胞建模系统来定义蛋白质对肿瘤发展的贡献的实用性。
How proteins participate in tumorigenesis can be obscured by their multifunctional nature. For example, depending on the cellular context, the cdk inhibitors can affect cell proliferation, cell motility, apoptosis, receptor tyrosine kinase signaling, and transcription. Thus, to determine how a protein contributes to tumorigenesis, we need to evaluate which functions are required in the developing tumor. Here we demonstrate that the RCAS/TvA system, originally developed to introduce oncogenes into somatic cells of mice, can be adapted to allow us to define the contribution that different functional domains make to tumor development. Studying the development of growth-factor-induced oligodendroglioma, we identified a critical role for the Cy elements in p21, and we showed that cyclin D1T286A, which accumulates in the nucleus of p21-deficient cells and binds to cdk4, could bypass the requirement for p21 during tumor development. These genetic results suggest that p21 acts through the cyclin D1–cdk4 complex to support tumor growth, and establish the utility of using a somatic cell modeling system for defining the contribution proteins make to tumor development.
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影响因子：
8
作者：
Fisher, GH;Orsulic, S;Varmus, HE
通讯作者：
Varmus, HE
影响因子：
11.4
作者：
Asada, M;Yamada, T;Mizutani, S
通讯作者：
Mizutani, S
影响因子：
10.5
作者：
Dai, C;Celestino, JC;Holland, EC
通讯作者：
Holland, EC
影响因子：
8.8
作者：
Baretton, GB;Klenk, U;Löhrs, U
通讯作者：
Löhrs, U
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.