From the Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8577, Japan.
J Biol Chem. 2014 Feb 21;289(8):4928-40. doi: 10.1074/jbc.M113.474049. Epub 2013 Dec 27.
Tetramerization of p53 is crucial to exert its biological activity, and nucleolar disruption is sufficient to activate p53. We previously demonstrated that nucleolar stress induces translocation of the nucleolar protein MYBBP1A from the nucleolus to the nucleoplasm and enhances p53 activity. However, whether and how MYBBP1A regulates p53 tetramerization in response to nucleolar stress remain unclear. In this study, we demonstrated that MYBBP1A enhances p53 tetramerization, followed by acetylation under nucleolar stress. We found that MYBBP1A has two regions that directly bind to lysine residues of the p53 C-terminal regulatory domain. MYBBP1A formed a self-assembled complex that provided a molecular platform for p53 tetramerization and enhanced p300-mediated acetylation of the p53 tetramer. Moreover, our results show that MYBBP1A functions to enhance p53 tetramerization that is necessary for p53 activation, followed by cell death with actinomycin D treatment. Thus, we suggest that MYBBP1A plays a pivotal role in the cellular stress response.
四聚化是 p53 发挥其生物学活性的关键，核仁破坏足以激活 p53。我们之前证明核仁应激诱导核仁蛋白 MYBBP1A 从核仁向核质易位，并增强 p53 活性。然而，MYBBP1A 是否以及如何调节 p53 四聚体化以响应核仁应激尚不清楚。在这项研究中，我们证明 MYBBP1A 增强了 p53 四聚体化，随后在核仁应激下发生乙酰化。我们发现 MYBBP1A 有两个区域可以直接结合 p53 C 端调节域赖氨酸残基。MYBBP1A 形成了一个自组装复合物，为 p53 四聚体化提供了分子平台，并增强了 p300 介导的 p53 四聚体的乙酰化。此外，我们的结果表明，MYBBP1A 发挥作用以增强 p53 四聚体化，这对于 p53 的激活是必需的，随后在 actinomycin D 处理时发生细胞死亡。因此，我们认为 MYBBP1A 在细胞应激反应中起着关键作用。
