INSERM U756, Faculté de Pharmacie, Université Paris-Sud 11, Châtenay-Malabry, France.
Autophagy. 2010 Jan;6(1):153-4. doi: 10.4161/auto.6.1.10537. Epub 2010 Jan 5.
p53 and JNK are two apoptosis-regulatory factors frequently deregulated in cancer cells and also involved in the modulation of autophagy. We have recently investigated the links between these two signalling pathways in terms of the regulation of autophagy. We showed that 2-methoxyestradiol (2-ME), an antitumoral compound, enhances autophagy and apoptosis in Ewing sarcoma cells through the activation of both p53 and JNK pathways. In this context, p53 regulates, at least partially, JNK activation which in turn modulates autophagy through two distinct mechanisms: on the one hand it promotes Bcl-2 phosphorylation resulting in the dissociation of the Beclin 1-Bcl-2 complex and on the other hand it leads to the upregulation of DRAM (Damage-Regulated Autophagy Modulator), a p53 target gene. The critical role of DRAM in 2-ME-mediated autophagy and apoptosis is underlined by the fact that its silencing efficiently prevents the induction of both processes. These findings not only report the interplay between JNK and p53 in the regulation of autophagy but also uncover the role of JNK activation in the regulation of DRAM, a pro-autophagic and proapoptotic protein.
p53 和 JNK 是两种在癌细胞中经常失调的凋亡调节因子，也参与自噬的调节。我们最近研究了这两条信号通路之间在自噬调节方面的联系。我们发现，2-甲氧基雌二醇（2-ME），一种抗肿瘤化合物，通过激活 p53 和 JNK 途径，增强尤文肉瘤细胞中的自噬和凋亡。在这种情况下，p53 至少部分调节 JNK 的激活，而 JNK 又通过两种不同的机制调节自噬：一方面，它促进 Bcl-2 的磷酸化，导致 Beclin 1-Bcl-2 复合物的解离；另一方面，它导致 DRAM（损伤调节自噬调节剂）的上调，DRAM 是 p53 的一个靶基因。DRAM 在 2-ME 介导的自噬和凋亡中的关键作用，其沉默有效地阻止了这两个过程的诱导。这些发现不仅报告了 JNK 和 p53 在自噬调节中的相互作用，还揭示了 JNK 激活在 DRAM 调节中的作用，DRAM 是一种促进自噬和促进凋亡的蛋白。
