The nucleolus directly regulates p53 export and degradation.
The nucleolus directly regulates p53 export and degradation.
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DOI：
10.1083/jcb.201105143
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发表时间：
2011-09-05
期刊：
影响因子：
--
通讯作者：
Rubbi CP
中科院分区：
文献类型：
--
作者：
Boyd MT;Vlatkovic N;Rubbi CP
核仁直接调节P53的输出和降解，而不是简单地隔离P53调节因子。应激诱导的核仁破坏和P53降解的消除之间的相关性在各种各样的细胞应激后是明显的。正如一些生化证据所表明的那样，这种联系可能是由核仁中发生的p53调控步骤引起的。或者，核仁的破坏也会导致核仁蛋白的重新分布，潜在地改变它们与P53和/或MDM2的相互作用。这提出了一个根本问题：核仁是直接控制P53，即作为P53调控过程发生的位置，还是间接控制P53/MDM2相互作用因子的细胞定位。在这项工作中，基于异核体、光漂白和微核的转运实验表明，p53调控事件直接由核仁调控，并依赖于完整的核仁结构和功能。亚细胞分离和核仁分离显示泛素化的P53的分布支持这些发现。此外，我们的结果表明，P53通过两条途径输出：一条是胁迫敏感的，另一条是胁迫不敏感的，后者受核仁中存在的活动调节。
Nucleoli directly regulate p53 export and degradation rather than simply sequestering p53 regulatory factors. 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.
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