ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth
ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth
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DOI：
10.1016/s1097-2765(03)00036-4
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发表时间：
2003-02-01
期刊：
影响因子：
16
通讯作者：
Grummt, I
中科院分区：
文献类型：
--
作者：
Zhao, J;Yuan, XJ;Grummt, I
通过丝裂原活化蛋白激酶（MAPK）级联的转录因子的磷酸化将细胞信号传导与基因表达的控制联系起来。在这里，我们表明，生长因子诱导rRNA的合成，通过激活MAPK依赖的信号级联，靶向RNA聚合酶I特异性转录起始因子TIF-1A。TIF-1A和核糖体基因转录的激活对PD 98059敏感，表明TIF-1A在体内被MAPK靶向。磷酸肽图谱和突变分析揭示了两个丝氨酸残基（S633和S649）被ERK和RSK激酶磷酸化。丙氨酸取代S649使TIF-1A失活，抑制前rRNA合成，并延缓细胞生长。这些结果提供了生长因子信号传导、核糖体产生和细胞生长之间的联系，并可能对细胞转化机制产生重大影响。
Phosphorylation of transcription factors by mitogen-activated protein kinase (MAPK) cascades links cell signaling with the control of gene expression. Here we show that growth factors induce rRNA synthesis by activating MAPK-dependent signaling cascades that target the RNA polymerase I-specific transcription initiation factor TIF-1A. Activation of TIF-1A and ribosomal gene transcription is sensitive to PD98059, indicating that TIF-1A is targeted by MAPK in vivo. Phosphopeptide mapping and mutational analysis reveals two serine residues (S633 and S649) that are phosphorylated by ERK and RSK kinases. Replacement of S649 by alanine inactivates TIF-1A, inhibits pre-rRNA synthesis, and retards cell growth. The results provide a link between growth factor signaling, ribosome production, and cell growth, and may have a major impact on the mechanism of cell transformation.