Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
J Cell Physiol. 2010 Nov;225(2):371-84. doi: 10.1002/jcp.22224.
The ubiquitin-like molecule, SUMO-1, a small protein essential for a variety of biological processes, is covalently conjugated to many intracellular proteins, especially to regulatory components of the transcriptional machinery, such as histones and transcription factors. Sumoylation provides either a stimulatory or an inhibitory signal for proliferation and for transcription, but the molecular mechanisms by which SUMO-1 achieves such versatility of effects are incompletely defined. The tumor suppressor and transcription regulator p53 is a relevant SUMO-1 target. Particularly, the C-terminal tail of p53 undergoes both sumoylation and acetylation. While the effects of sumoylation are still controversial, acetylation modifies p53 interaction with chromatin embedded promoters, and enforces p53 apoptotic activity. In this study, we show that the N-terminal region of SUMO-1 might functionally mimic this activity of the p53 C-terminal tail. We found that this SUMO-1 domain possesses similarity with the C-terminal acetylable p53 tail as well as with acetylable domains of other transcription factors. SUMO-1 is, indeed, acetylated when conjugated to its substrates and to p53. In the acetylable form SUMO-1 tunes the p53 response by modifying p53 transcriptional program, by promoting binding onto selected promoters and by favoring apoptosis. By contrast, when non-acetylable, SUMO-1 enforces cell-cycle arrest and p53 binding to a different sets of genes. These data demonstrate for the first time that SUMO-1, a post-translational modification is, in turn, modified by acetylation. Further, they imply that the pleiotropy of effects by which SUMO-1 influences various cellular outcomes and the activity of p53 depends upon its acetylation state.
泛素样分子 SUMO-1 是一种对多种生物过程至关重要的小蛋白，它可共价结合到许多细胞内蛋白上，尤其是转录机制的调节成分，如组蛋白和转录因子。SUMO 化可作为增殖和转录的刺激或抑制信号，但 SUMO-1 实现这种多功能效应的分子机制尚未完全定义。肿瘤抑制因子和转录调节因子 p53 是相关的 SUMO-1 靶标。特别是，p53 的 C 端尾部经历 SUMO 化和乙酰化。虽然 SUMO 化的作用仍存在争议，但乙酰化改变了 p53 与嵌入染色质的启动子的相互作用，并增强了 p53 的凋亡活性。在这项研究中，我们表明 SUMO-1 的 N 端区域可能在功能上模拟 p53 C 端尾部的这种活性。我们发现，该 SUMO-1 结构域与 C 端可乙酰化的 p53 尾部以及其他转录因子的可乙酰化结构域具有相似性。当 SUMO-1 与底物和 p53 结合时，它会被乙酰化。在可乙酰化形式下，SUMO-1 通过修饰 p53 转录程序、促进与选定启动子的结合以及促进凋亡来调节 p53 反应。相比之下，当非乙酰化时，SUMO-1 会导致细胞周期停滞，并使 p53 结合到不同的基因集。这些数据首次证明，作为一种翻译后修饰的 SUMO-1 本身可被乙酰化修饰。此外，它们意味着 SUMO-1 通过影响各种细胞结果和 p53 活性的多效性取决于其乙酰化状态。
