Autophagic activity dictates the cellular response to oncogenic RAS.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Wang, XD; Lapi, E; Sullivan, A; Jia, W; He, Y-W; Ratnayaka, I; Zhong, S; Goldin, RD; Goemans, CG; Tolkovsky, AM; Lu, X

Published Date

  • August 14, 2012

Published In

Volume / Issue

  • 109 / 33

Start / End Page

  • 13325 - 13330

PubMed ID

  • 22847423

Pubmed Central ID

  • PMC3421174

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1120193109


  • eng

Conference Location

  • United States