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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The role of B′ subunits as tumor suppressors is corroborated by the notion that B′ subunit knockdown causes polyploidy.
“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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- 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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