Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA
Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA
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DOI：
10.1073/pnas.1313097110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Mitchell, Beverly S.
中科院分区：
文献类型：
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作者：
Le Xuan Truong Nguyen;Mitchell, Beverly S.
转录起始因子I （Transcription initiation factor I, tifi - ia）通过将RNA聚合酶I （RNA polymerase I, Pol I）拴在rDNA启动子上，在调控核糖体RNA （rRNA）合成中发挥重要作用。我们发现活化的Akt通过酪蛋白激酶II α (CK2 α)在其N端附近苏氨酸残基上的磷酸化来增强rRNA的合成。CK2反过来磷酸化tifi - ia，从而增加rDNA转录。活化的Akt还能稳定tifi - ia，诱导其易位到核核，并增强其与Pol i的相互作用。用AZD8055 （Akt和哺乳动物雷帕霉素磷酸化靶点的抑制剂，但不与雷帕霉素一起作用）处理，会破坏Akt介导的tifi - ia的稳定性、易位和活性。这些数据支持一个模型，在这个模型中，激活的Akt通过阻止TIF-IA降解和磷酸化CK2 α来增强rRNA合成，而CK2 α反过来又磷酸化TIF-IA。该模型解释了活化Akt促进细胞增殖和潜在转化的能力。
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 II alpha (CK2 alpha) 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 CK2 alpha, which in turn phosphorylates TIF-IA. This model provides an explanation for the ability of activated Akt to promote cell proliferation and, potentially, transformation.