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首页> 外文期刊>Molecular and Cellular Biology >Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression.
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Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression.

机译：E2F家族成员的表达失调诱导S期进入并克服了p16INK4A介导的生长抑制。

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The E2F family of transcription factors regulate genes, whose products are essential for progression through the mammalian cell cycle. The transcriptional activity of the E2Fs is inhibited through the specific binding of the retinoblastoma protein, pRB, and the pRB homologs p107 and p130 to their transactivation domains. Seven members of the E2F transcription factor family have been isolated so far, and we were interested in investigating the possible contribution of the various E2Fs to cell cycle control. By presenting the results of the generation of cell lines with tetracycline-controlled expression of E2F-1 and E2F-4 and microinjection of expression plasmids for all members of the E2F family, we demonstrate here that the pRB-associated ED2Fs (E2F-1, E2F-2, and E2F-3) all induce S phase in quiescent rate fibroblasts when expressed alone. In contrast, the p107/p130-associated E2Fs require the coexpression of the heterodimeric partner DP-1 to promote S-phase entry and accelerate G1 progression. Furthermore, the pRB-associated E2Fs were all able to overcome a G1 arrest mediated by the p16INK4 tumor suppressor protein, and E2F-1 was shown to override a G1 block mediated by a neutralizing antibody to cyclin D1. The p16INK4-induced G1 arrest was not affected by expression of E2F-4, E2F-5, or DP-1 alone, but simulataneous expression of E2F-4 and DP-1 could overcome this block. Our results demonstrate that the generation of E2F activity is rate limiting for G1 progession, is sufficient to induce S-phase entry, and overcomes a p16-mediated G1 block, and since E12F-1, E2F-2, and E2F-3 are associated with pRB, they are the most likely downstream effectors in the p126-cyclin D-pRB pathway. Furthermore, our date suggest that the two subsets of E2Fs are regulated by distinct mechanisms and/or that they have distinct functions in cell cycle control. Since E2F-4 and E2F-5 cannot promote S-phase entry by themselves, our results may provide an explanation for the apparent lack of aberrations in p107 or p130 in human cancer.
机译：E2F转录因子家族调节基因，其产物对于通过哺乳动物细胞周期的进展至关重要。 E2Fs的转录活性通过成视网膜细胞瘤蛋白pRB和pRB同源物p107和p130与其反式激活域的特异性结合而受到抑制。到目前为止，已分离出E2F转录因子家族的7个成员，我们对研究各种E2F对细胞周期控制的可能贡献感兴趣。通过介绍具有E2F-1和E2F-4的四环素控制表达的细胞系的生成结果以及E2F家族所有成员的表达质粒的显微注射，我们在此证明了pRB相关的ED2F（E2F-1，当单独表达时，E2F-2和E2F-3）均会在静态速率的成纤维细胞中诱导S期。相反，与p107 / p130相关的E2F需要异二聚体伴侣DP-1的共表达，以促进S期进入并加速G1进程。此外，与pRB相关的E2F都能够克服由p16INK4肿瘤抑制蛋白介导的G1阻滞，并且显示E2F-1覆盖由针对细胞周期蛋白D1的中和抗体介导的G1阻滞。 p16INK4诱导的G1阻滞不受单独的E2F-4，E2F-5或DP-1表达的影响，但是E2F-4和DP-1的同时表达可以克服这一障碍。我们的结果表明，E2F活性的产生限制了G1的增殖，足以诱导S期进入，并克服了p16介导的G1阻滞，并且由于E12F-1，E2F-2和E2F-3相关使用pRB，它们是p126-cyclin D-pRB途径中最可能的下游效应子。此外，我们的数据表明，E2F的两个子集受不同机制调控和/或在细胞周期控制中具有不同功能。由于E2F-4和E2F-5本身不能促进S期进入，因此我们的结果可能解释了人类癌症中p107或p130明显缺乏像差。

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