title: 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((Δ3/Δ3)) 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.
authors: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine,  University of Oxford, Oxford OX3 7DQ,  United Kingdom.
authors: Yihua
authors: Y
authors: Wang
authors: Xiao Dan
authors: XD
authors: Wang
authors: Eleonora
authors: E
authors: Lapi
authors: Alexandra
authors: A
authors: Sullivan
authors: Wei
authors: W
authors: Jia
authors: You-Wen
authors: YW
authors: He
authors: Indrika
authors: I
authors: Ratnayaka
authors: Shan
authors: S
authors: Zhong
authors: Robert D
authors: RD
authors: Goldin
authors: Christoph G
authors: CG
authors: Goemans
authors: Aviva M
authors: AM
authors: Tolkovsky
authors: Xin
authors: X
authors: Lu
mesh_terms: D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D016922:Cellular Senescence; D004625:Embryo, Nonmammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009857:Oncogenes; D011485:Protein Binding; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C491971:Atg12 protein, mouse; C495773:Atg5 protein, mouse; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C511437:Trp53bp2 protein, mouse; D025521:Tumor Suppressor Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)