Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells
Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells
复制标题
DOI：
10.1038/sj.onc.1208590
复制
发表时间：
2005-06-16
期刊：
影响因子：
8
通讯作者：
Dunn, SE
中科院分区：
文献类型：
--
作者：
Sutherland, BW;Kucab, J;Dunn, SE
Akt/PKB是一种丝氨酸/苏氨酸激酶，通过磷酸化转录因子和细胞周期蛋白促进肿瘤细胞生长。人们特别感兴趣的是寻找Akt的肿瘤特异性底物，以了解这种蛋白质在癌症中的功能，并为治疗靶向提供新的途径。我们的实验室试图鉴定在乳腺癌中表达的新型Akt底物。在这项研究中，我们确定激活Akt与转录/翻译因子Y-box结合蛋白-1（YB-1）的蛋白表达在原发性乳腺癌中通过筛选肿瘤组织微阵列呈正相关。因此，我们质疑Akt和YB-1是否可能在功能上相关联。在此，我们说明激活的Akt结合并磷酸化YB-1冷休克结构域的Ser 102。然后，我们通过将Ser 102突变为Ala 102来解决破坏Ser 102的功能意义。在MCF-7细胞中稳定表达Flag：YB-1和Flag：YB-1（Ala 102）后，我们观察到YB-1上Akt磷酸化位点的破坏抑制了软琼脂和单层中的肿瘤细胞生长。这与YB-1（Ala 102）突变体对核转位的抑制有关。总之，YB-1是一种新的Akt底物，破坏该特异性位点可抑制肿瘤细胞生长。
Akt/PKBis a serine/threonine kinase that promotes tumor cell growth by phosphorylating transcription factors and cell cycle proteins. There is particular interest in finding tumor-specific substrates for Akt to understand how this protein functions in cancer and to provide new avenues for therapeutic targeting. Our laboratory sought to identify novel Akt substrates that are expressed in breast cancer. In this study, we determined that activated Akt is positively correlated with the protein expression of the transcription/translation factor Y-box binding protein-1 (YB-1) in primary breast cancer by screening tumor tissue microarrays. We therefore questioned whether Akt and YB-1 might be functionally linked. Herein, we illustrate that activated Akt binds to and phosphorylates the YB-1 cold shock domain at Ser102. We then addressed the functional significance of disrupting Ser102 by mutating it to Ala102. Following the stable expression of Flag: YB-1 and Flag: YB-1 ( Ala102) in MCF-7 cells, we observed that disruption of the Akt phosphorylation site on YB-1 suppressed tumor cell growth in soft agar and in monolayer. This correlated with an inhibition of nuclear translocation by the YB-1( Ala102) mutant. In conclusion, YB-1 is a new Akt substrate and disruption of this specific site inhibits tumor cell growth.