title: Chaperone-mediated autophagy degrades mutant p53.
abstract: 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Helin
authors.initials: H
authors.lastname: Vakifahmetoglu-Norberg
authors.forename: Minsu
authors.initials: M
authors.lastname: Kim
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Xia
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Iwanicki
authors.forename: Dimitry
authors.initials: D
authors.lastname: Ofengeim
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.forename: Lifeng
authors.initials: L
authors.lastname: Pan
authors.forename: Tan A
authors.initials: TA
authors.lastname: Ince
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007976:Leupeptins; D018832:Molecular Chaperones; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: CMA; autophagy; cancer; p53; spautin-1
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