Department of Medicine and Department of Chemical and Systems Biology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20681-6. doi: 10.1073/pnas.1313097110. Epub 2013 Dec 2.
Transcription initiation factor I (TIF-IA) plays an essential role in regulating ribosomal RNA (rRNA) synthesis by tethering RNA polymerase I (Pol I) to the rDNA promoter. We have found that activated Akt enhances rRNA synthesis through the phosphorylation of casein kinase IIα (CK2α) on a threonine residue near its N terminus. CK2 in turn phosphorylates TIF-IA, thereby increasing rDNA transcription. Activated Akt also stabilizes TIF-IA, induces its translocation to the nucleolus, and enhances its interaction with Pol I. Treatment with AZD8055, an inhibitor of both Akt and mammalian target of rapamycin phosphorylation, but not with rapamycin, disrupts Akt-mediated TIF-IA stability, translocation, and activity. These data support a model in which activated Akt enhances rRNA synthesis both by preventing TIF-IA degradation and phosphorylating CK2α, which in turn phosphorylates TIF-IA. This model provides an explanation for the ability of activated Akt to promote cell proliferation and, potentially, transformation.
转录起始因子 I（TIF-IA）通过将 RNA 聚合酶 I（Pol I）与 rDNA 启动子连接在一起，在调节核糖体 RNA（rRNA）合成中发挥着重要作用。我们发现，激活的 Akt 通过其 N 端附近一个苏氨酸残基上的磷酸化作用来增强 CK2α（酪蛋白激酶 IIα）的活性，从而促进 rRNA 的合成。反过来，CK2 磷酸化 TIF-IA，从而增加 rDNA 的转录。激活的 Akt 还稳定 TIF-IA，诱导其向核仁易位，并增强其与 Pol I 的相互作用。用 Akt 和哺乳动物雷帕霉素靶蛋白磷酸化的双重抑制剂 AZD8055 处理，但不用雷帕霉素处理，会破坏 Akt 介导的 TIF-IA 稳定性、易位和活性。这些数据支持了一个模型，即激活的 Akt 通过防止 TIF-IA 降解和磷酸化 CK2α 来增强 rRNA 的合成，而 CK2α 又反过来磷酸化 TIF-IA。该模型解释了激活的 Akt 促进细胞增殖并可能促进转化的能力。
