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Autophagic activity dictates the cellular response to oncogenic RAS.

ABSTRACT: RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2((?3/?3)) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3421174 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Autophagic activity dictates the cellular response to oncogenic RAS.

Wang Yihua Y Wang Xiao Dan XD Lapi Eleonora E Sullivan Alexandra A Jia Wei W He You-Wen YW Ratnayaka Indrika I Zhong Shan S Goldin Robert D RD Goemans Christoph G CG Tolkovsky Aviva M AM Lu Xin X

Proceedings of the National Academy of Sciences of the United States of America 20120730 33

RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2((Δ3/Δ3)) mouse embryonic fibroblasts that escape senescence express a ...[more]

PMID: 22847423

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Autophagic activity dictates the cellular response to oncogenic RAS.

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Autophagic activity dictates the cellular response to oncogenic RAS.

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