Di Giovanni Simone, Knights Chad D, Rao Mahadev, Yakovlev Alexander, Beers Jeannette, Catania Jason, Avantaggiati Maria Laura, Faden Alan I
Laboratory for NeuroRegeneration and Repair, Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany.
EMBO J. 2006 Sep 6;25(17):4084-96. doi: 10.1038/sj.emboj.7601292. Epub 2006 Aug 31.
Axon regeneration is substantially regulated by gene expression and cytoskeleton remodeling. Here we show that the tumor suppressor protein p53 is required for neurite outgrowth in cultured cells including primary neurons as well as for axonal regeneration in mice. These effects are mediated by two newly identified p53 transcriptional targets, the actin-binding protein Coronin 1b and the GTPase Rab13, both of which associate with the cytoskeleton and regulate neurite outgrowth. We also demonstrate that acetylation of lysine 320 (K320) of p53 is specifically involved in the promotion of neurite outgrowth and in the regulation of the expression of Coronin 1b and Rab13. Thus, in addition to its recognized role in neuronal apoptosis, surprisingly, p53 is required for neurite outgrowth and axonal regeneration, likely through a different post-translational pathway. These observations may suggest a novel therapeutic target for promoting regenerative responses following peripheral or central nervous system injuries.
轴突再生受到基因表达和细胞骨架重塑的显著调控。在此我们表明，肿瘤抑制蛋白p53对于包括原代神经元在内的培养细胞中的神经突生长以及小鼠的轴突再生都是必需的。这些作用是由两个新鉴定出的p53转录靶点介导的，即肌动蛋白结合蛋白冠蛋白1b和GTP酶Rab13，二者均与细胞骨架相关并调节神经突生长。我们还证明，p53赖氨酸320（K320）的乙酰化特异性地参与促进神经突生长以及调节冠蛋白1b和Rab13的表达。因此，令人惊讶的是，除了其在神经元凋亡中公认的作用外，p53对于神经突生长和轴突再生也是必需的，可能是通过一条不同的翻译后途径。这些观察结果可能提示了一个促进外周或中枢神经系统损伤后再生反应的新治疗靶点。
