Evidence for the interplay between JNK and p53-DRAM signalling pathways in the regulation of autophagy

Abstract

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.