Dissecting the pathways that destabilize mutant p53: The proteasome or autophagy?

摘要: One fundamental feature of mutant forms p53 consists in their accumulation at high levels tumors. At least the case neomorphic mutations, which acquire oncogenic activity, stabilization is a driving force for tumor progression. It well documented that mutants are resistant to proteasome-dependent degradation compared with wild-type p53, but exact identity pathways affect stability still debated. We have recently shown macroautophagy (autophagy) provides route during restriction glucose. Here we further show basal conditions growth, inhibition autophagy chemical inhibitors or by downregulation essential autophagic genes ATG1/Ulk1, Beclin-1 ATG5, results stabilization. Conversely, overexpression ATG1/Ulk1 leads depletion. Furthermore, found many cell lines, prolonged proteasome does not stabilize its autophagic-mediated degradation. Therefore, conclude key mechanism regulating several mutants. discuss plausible mechanisms involved this newly identified pathway as possible role played evolution driven p53.