Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
EMBO J. 2011 Mar 16;30(6):1054-66. doi: 10.1038/emboj.2011.23. Epub 2011 Feb 4.
A number of external and internal insults disrupt nucleolar structure, and the resulting nucleolar stress stabilizes and activates p53. We show here that nucleolar disruption induces acetylation and accumulation of p53 without phosphorylation. We identified three nucleolar proteins, MYBBP1A, RPL5, and RPL11, involved in p53 acetylation and accumulation. MYBBP1A was tethered to the nucleolus through nucleolar RNA. When rRNA transcription was suppressed by nucleolar stress, MYBBP1A translocated to the nucleoplasm and facilitated p53-p300 interaction to enhance p53 acetylation. We also found that RPL5 and RPL11 were required for rRNA export from the nucleolus. Depletion of RPL5 or RPL11 blocked rRNA export and counteracted reduction of nucleolar RNA levels caused by inhibition of rRNA transcription. As a result, RPL5 or RPL11 depletion inhibited MYBBP1A translocation and p53 activation. Our observations indicated that a dynamic equilibrium between RNA generation and export regulated nucleolar RNA content. Perturbation of this balance by nucleolar stress altered the nucleolar RNA content and modulated p53 activity.
许多内外因素的侵害会破坏核仁结构，由此产生的核仁应激会稳定并激活 p53。我们在此表明，核仁破坏会导致 p53 乙酰化和积累，而不会使其磷酸化。我们鉴定出三种参与 p53 乙酰化和积累的核仁蛋白，即 MYBBP1A、RPL5 和 RPL11。MYBBP1A 通过核仁 RNA 与核仁结合。当核仁应激抑制 rRNA 转录时，MYBBP1A 易位到核质中，并促进 p53-p300 相互作用，从而增强 p53 乙酰化。我们还发现 RPL5 和 RPL11 对于 rRNA 从核仁输出是必需的。RPL5 或 RPL11 的耗竭会阻断 rRNA 输出，并抵消 rRNA 转录抑制引起的核仁 RNA 水平降低。结果，RPL5 或 RPL11 的耗竭抑制了 MYBBP1A 的易位和 p53 的激活。我们的观察结果表明，RNA 生成和输出之间的动态平衡调节核仁 RNA 含量。核仁应激对这种平衡的干扰改变了核仁 RNA 含量并调节了 p53 活性。
