Autophagic activity dictates the cellular response to oncogenic RAS

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 Apop...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-08, Vol.109 (33), p.13325-13330
Main Authors: Wang, Yihua, Wang, Xiao Dan, Lapi, Eleonora, Sullivan, Alexandra, Jia, Wei, He, You-Wen, Ratnayaka, Indrika, Zhong, Shan, Goldin, Robert D, Goemans, Christoph G, Tolkovsky, Aviva M, Lu, Xin
Format: Article
Language:English
Subjects:
Aging
Animals
Apoptosis
Autophagy
Autophagy-Related Protein 12
Autophagy-Related Protein 5
Biological Sciences
carcinogenesis
Cell growth
Cell lines
Cells
Cellular Senescence
Embryo, Nonmammalian - cytology
Epithelial cells
fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
Gene expression regulation
gene overexpression
HCT116 cells
Humans
Infections
Mice
Microtubule-Associated Proteins - metabolism
Multiprotein Complexes - metabolism
mutants
neoplasms
Oncogenes
Protein Binding
Protein Stability
Proteins
Proteins - metabolism
Proto-Oncogene Proteins p21(ras) - metabolism
Rodents
T lymphocytes
Tumor Suppressor Proteins - chemistry
Tumor Suppressor Proteins - metabolism
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1120193109