Autophagic activity dictates the cellular response to oncogenic RAS
- 30 July 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (33), 13325-13330
- https://doi.org/10.1073/pnas.1120193109
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.Keywords
This publication has 31 references indexed in Scilit:
- Autophagy: an adaptable modifier of tumourigenesisCurrent Opinion in Genetics & Development, 2010
- The Rac1/MKK7/JNK pathway signals upregulation of Atg5 and subsequent autophagic cell death in response to oncogenic RasCarcinogenesis: Integrative Cancer Research, 2009
- Autophagy mediates the mitotic senescence transitionGenes & Development, 2009
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagy: Basic Principles and Relevance to DiseaseAnnual review of pathology, 2008
- Drosophila ASPP Regulates C-Terminal Src Kinase ActivityDevelopmental Cell, 2007
- Solution Structure of ASPP2 N-terminal Domain (N-ASPP2) Reveals a Ubiquitin-like FoldJournal of Molecular Biology, 2007
- Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha- RAS -transformed human colon cellsCarcinogenesis: Integrative Cancer Research, 2006
- ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growthGenes & Development, 2006
- Autophagy and Cancer TherapyAutophagy, 2006