Chaperone-mediated autophagy degrades mutant p53

• Published in: Genes & development Vol. 27; no. 15; pp. 1718 - 1730
• Main Authors: Vakifahmetoglu-Norberg, Helin, Kim, Minsu, Xia, Hong-Guang, Iwanicki, Marcin P, Ofengeim, Dimitry, Coloff, Jonathan L, Pan, Lifeng, Ince, Tan A, Kroemer, Guido, Brugge, Joan S, Yuan, Junying
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-08-2013
• Subjects: Antineoplastic Agents - pharmacology; Autophagy - drug effects; Autophagy - genetics; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Gene Expression Regulation, Neoplastic - drug effects; Humans; Leupeptins - pharmacology; Lysosomes - metabolism; Molecular Chaperones - metabolism; Mutation; Proteasome Endopeptidase Complex - drug effects; Proteolysis - drug effects; Pyrazines - pharmacology; Research Paper; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitination; cancer; autophagy; spautin-1; CMA; p53
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.220897.113

Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to tumor development and metastasis. Thus, promoting the removal of mutant p53 proteins in cancer cells may have therapeutic significance. Here we investigated the mechanisms that govern the turnover of mutant p53 in nonproliferating tumor cells using a combination of pharmacological and genetic approaches. We show that suppression of macroautophagy by multiple means promotes the degradation of mutant p53 through chaperone-mediated autophagy in a lysosome-dependent fashion. In addition, depletion of mutant p53 expression due to macroautophagy inhibition sensitizes the death of dormant cancer cells under nonproliferating conditions. Taken together, our results delineate a novel strategy for killing tumor cells that depend on mutant p53 expression by the activation of chaperone-mediated autophagy and potential pharmacological means to reduce the levels of accumulated mutant p53 without the restriction of mutant p53 conformation in quiescent tumor cells.