Brenet F, Socci N D, Sonenberg N, Holland E C
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Oncogene. 2009 Jan 8;28(1):128-39. doi: 10.1038/onc.2008.376. Epub 2008 Oct 6.
The Akt signaling pathway activity increases as normal tissue progresses to malignant transformation, and regulates the translation of specific messenger RNAs (mRNAs) through multiple mechanisms. We have identified one such mechanism of Akt-dependent translation control as involving the lupus autoantigen La. La is an RNA-associated protein that contains multiple trafficking elements to support the interaction with RNAs in different subcellular locations. We show here that the La protein is a direct target of the serine/threonine protein kinase Akt on threonine 301, and La nuclear export in mouse glial progenitors, as well as its association with polysomes is modulated by Akt activity. Using a functional approach to determine the network of genes affected by La in the cytoplasm by microarray analysis of polysome-bound mRNAs, we found that La binds 34% of the polysome bound mRNAs and regulates the expression of a specific pool of mRNAs under KRas/Akt activation. Therefore, La appears to be an important contributor to Akt-mediated translational regulation of these transcripts in murine glial cells.
随着正常组织向恶性转化的进展，Akt信号通路活性增加，并通过多种机制调节特定信使核糖核酸（mRNA）的翻译。我们已经确定了一种Akt依赖性翻译控制机制，该机制涉及狼疮自身抗原La。La是一种与RNA相关的蛋白质，含有多个转运元件，以支持其与不同亚细胞位置的RNA相互作用。我们在此表明，La蛋白是丝氨酸/苏氨酸蛋白激酶Akt在苏氨酸301位点的直接靶点，并且在小鼠神经胶质祖细胞中，La的核输出及其与多核糖体的结合受Akt活性调节。通过对与多核糖体结合的mRNA进行微阵列分析，采用功能方法确定细胞质中受La影响的基因网络，我们发现La结合34%的与多核糖体结合的mRNA，并在KRas/Akt激活下调节特定mRNA池的表达。因此，La似乎是小鼠神经胶质细胞中Akt介导的这些转录本翻译调控的重要贡献者。
