Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation
Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation
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DOI：
10.1128/mcb.25.6.2095-2106.2005
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发表时间：
2005-03-01
影响因子：
5.3
通讯作者：
Vogt, PK
中科院分区：
文献类型：
--
作者：
Bader, AG;Vogt, PK
多功能Y盒结合蛋白1 （YB-1）被致癌磷酸肌醇激酶（PI3K）通路转录抑制（P3K是催化亚基的致癌同源物），当用逆转录病毒载体RCAS重新表达时，会干扰P3K和akt诱导的鸡胚成纤维细胞转化。逆转录病毒表达的YB-1结合到mrna的帽上，抑制帽依赖性和帽非依赖性翻译。为了确定YB-1在p3k诱导的转化中抑制作用的要求，我们进行了突变分析，测量了YB-1诱导的转化干扰、亚细胞定位、帽结合、mRNA结合、同二聚体化和翻译抑制。结果表明：(1)对转化的干扰需要RNA结合和与细胞质保留域不同的c端结构域，(2)对转化的干扰与翻译的抑制密切相关，(3)YB-1对mrna的屏蔽不足以阻断转化或抑制翻译。我们在YB-1的c端发现了一个非规范核定位信号（NLS）。缺乏NLS的突变体保留了干扰转化的能力，这表明不需要核功能。这些结果表明，YB-1通过其rna结合域和c端域的一个区域特异性抑制翻译，从而干扰p3k诱导的转化。讨论了c端区域的势函数。
The multifunctional Y box-binding protein 1 (YB-1) is transcriptionally repressed by the oncogenic phosphoinositide 3-kinase (PI3K) pathway (with P3K as an oncogenic homolog of the catalytic subunit) and, when reexpressed with the retroviral vector RCAS, interferes with P3K- and Akt-induced transformation of chicken embryo fibroblasts. Retrovirally expressed YB-1 binds to the cap of mRNAs and inhibits cap-dependent and cap-independent translation. To determine the requirements for the inhibitory role of YB-1 in P3K-induced transformation, we conducted a mutational analysis, measuring YB-1-induced interference with transformation, subcellular localization, cap binding, mRNA binding, homodimerization, and inhibition of translation. The results show that (i) interference with transformation requires RNA binding and a C-terminal domain that is distinct from the cytoplasmic retention domain, (ii) interference with transformation is tightly correlated with inhibition of translation, and (iii) masking of mRNAs by YB-1 is not sufficient to block transformation or to inhibit translation. We identified a noncanonical nuclear localization signal (NLS) in the C-terminall half of YB-1. A mutant lacking the NLS retains its ability to interfere with transformation, indicating that a nuclear function is not required. These results suggest that YB-1 interferes with P3K-induced transformation by a specific inhibition of translation through its RNA-binding domain and a region in the C-terminal domain. Potential functions of the C-terminal region are discussed.