p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, England, UK.
J Cell Biol. 2011 Sep 5;194(5):689-703. doi: 10.1083/jcb.201105143.
The correlation between stress-induced nucleolar disruption and abrogation of p53 degradation is evident after a wide variety of cellular stresses. This link may be caused by steps in p53 regulation occurring in nucleoli, as suggested by some biochemical evidence. Alternatively, nucleolar disruption also causes redistribution of nucleolar proteins, potentially altering their interactions with p53 and/or MDM2. This raises the fundamental question of whether the nucleolus controls p53 directly, i.e., as a site where p53 regulatory processes occur, or indirectly, i.e., by determining the cellular localization of p53/MDM2-interacting factors. In this work, transport experiments based on heterokaryons, photobleaching, and micronucleation demonstrate that p53 regulatory events are directly regulated by nucleoli and are dependent on intact nucleolar structure and function. Subcellular fractionation and nucleolar isolation revealed a distribution of ubiquitylated p53 that supports these findings. In addition, our results indicate that p53 is exported by two pathways: one stress sensitive and one stress insensitive, the latter being regulated by activities present in the nucleolus.
应激诱导核仁解体与 p53 降解受阻之间的相关性在多种细胞应激后是明显的。这种联系可能是由核仁中 p53 调节步骤引起的，一些生化证据也表明了这一点。或者，核仁的破坏也会导致核仁蛋白的重新分布，从而可能改变它们与 p53 和/或 MDM2 的相互作用。这就提出了一个基本问题，即核仁是否直接控制 p53，即作为 p53 调节过程发生的场所，或者间接地通过决定 p53/MDM2 相互作用因子的细胞定位来控制 p53。在这项工作中，基于异核体的运输实验、光漂白和微核形成实验表明，p53 调节事件直接受到核仁的调控，并且依赖于完整的核仁结构和功能。亚细胞分级分离和核仁分离显示了支持这些发现的泛素化 p53 的分布。此外，我们的结果表明，p53 通过两种途径进行输出：一种对应激敏感，一种对应激不敏感，后者受核仁中存在的活性调节。
