The DOI matches its Crossref record; 39 of the 42 references it cites were found in a registry or an index.
A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells
Abstract
The stability of c-Myc is regulated by multiple Ras effector pathways. Phosphorylation at Ser 62 stabilizes c-Myc, whereas subsequent phosphorylation at Thr 58 is required for its degradation. Here we show that Ser 62 is dephosphorylated by protein phosphatase 2A (PP2A) before ubiquitination of c-Myc, and that PP2A activity is regulated by the Pin1 prolyl isomerase. Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc. A stable c-Myc(T58A) mutant that cannot bind Pin1 or be dephosphorylated by PP2A replaces SV40 small T antigen in human cell transformation and tumorigenesis assays. Therefore, small T antigen, which inactivates PP2A, exerts its oncogenic potential by preventing dephosphorylation of c-Myc, resulting in c-Myc stabilization. Thus, Ras-dependent signalling cascades ensure transient and self-limiting accumulation of c-Myc, disruption of which contributes to human cell oncogenesis.
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“This notion corroborates with the previous notion on the role of B′ subunits as tumor suppressors [45–49].”
From PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis (2017) · cites this paper as [48]
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Self-citationMultiple Ras-dependent phosphorylation pathways regulate Myc protein stabilityPreprint
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Metadata
- Authors
- Yeh, E., Cunningham, M., Arnold, H., Chasse, D., Monteith, T., Ivaldi, G., Hahn, W. C., Stukenberg, P. T., Shenolikar, S., Uchida, T., Counter, C. M., Nevins, J. R., Means, A. R., & Sears, R.
- Affiliations
- Duke Medical Center (US)
- Oregon Health & Science University (US)
- Howard Hughes Medical Institute (US)
- Duke University (US)
- Brigham and Women's Hospital (US)
- University of Virginia (US)
- Tohoku University (JP)
- Corresponding author
- Sears, Rosalie
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2004-03-14
- Volume
- 6
- Issue
- 4
- Pages
- 308-318
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2105214585
- Cited by
- 791
- References
- 42
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 27 · 2023: 29 · 2022: 24 · 2021: 40 · 2020: 42 · 2019: 33 · 2018: 30 · 2017: 32 · 2016: 37 · 2015: 39 · 2014: 53 · 2013: 39 · 2012: 31
- FWCI
- 16.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (K01CA086957, CA 100855, R01CA082845, CA 86957, CA 82845, R01CA100855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- c-Myc, protein stability, protein phosphatase 2A, ubiquitination, Ras signaling, oncogenic transformation, SV40 small t antigen, carcinogenesis
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Amino Acid Sequence, Animals, Antigens, Polyomavirus Transforming, Cell Line, Cell Transformation, Neoplastic, Humans, Mutation, Neoplasms, Phosphoprotein Phosphatases, Phosphorylation, Serine, Threonine, Signal Transduction, Genes, myc, Proto-Oncogene Proteins c-myc, Peptidylprolyl Isomerase, RNA Stability, Mice, Rats, Protein Phosphatase 2
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