The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Autophagic activity dictates the cellular response to oncogenic RAS
Open accessAbstract
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.
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“Indeed, some studies have shown that inhibition of autophagy facilitates senescence (Kang et al. 2011a; Wang et al. 2012), but this might be due in part to the loss of cell-protective roles of autophagy, which facilitates senescence effectors under some stressful conditions, where cells are not prone to apoptosis.”
From Cellular senescence and its effector programs (2014) · cites this paper as Wang et al. 2012
Citations
Cites
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“ASPP2( 3/ 3) + RAS Tu m or W ei gh t ( g) vector (1-1128)(1-360) (123-1128) 0 20 40 60 ASPP2( 3/ 3) + RAS”
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Self-citationActivated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
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Mariño, G., Niso-Santano, M., Baehrecke, E. H., & Kroemer, G. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3735 · Cited by 2,172
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232
Autophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855
Biomarkers, oxidative stress and autophagy in skin aging
Gu, Y., Han, J., Jiang, C., & Zhang, Y. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101036 · Cited by 797
Metadata
- Authors
- Wang, Y., Wang, X. D., Lapi, E., Sullivan, A., Jia, W., He, Y.-W., Ratnayaka, I., Zhong, S., Goldin, R. D., Goemans, C. G., Tolkovsky, A. M., & Lu, X.
- Affiliations
- University of Oxford (GB)
- Duke Medical Center (US)
- Imperial College London (GB)
- University of Cambridge (GB)
- Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-30
- Volume
- 109
- Issue
- 33
- Pages
- 13325-13330
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3421174
- OpenAlex
- W2074957956
- Cited by
- 117
- References
- 31
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 13 · 2021: 9 · 2020: 4 · 2019: 7 · 2018: 12 · 2017: 11 · 2016: 9 · 2015: 9 · 2014: 18 · 2013: 8 · 2012: 3
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute of Allergy and Infectious Diseases (R01AI074944)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- oncogenic Ras, autophagy, cellular senescence, ASPP2, ATG5, ATG12, Atg16, ATG3, mouse embryonic fibroblasts, Ras-induced senescence, carcinogenesis, p53
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 12, Animals, Autophagy, Embryo, Nonmammalian, Fibroblasts, Humans, Microtubule-Associated Proteins, Oncogenes, Protein Binding, Proteins, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, Protein Stability
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