Cited by 796Signaling Pathways in DiseaseProtein Kinase Regulation and GTPase SignalingCancer-related Molecular Pathways

A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells

Yeh, Elizabeth, Cunningham, Melissa, Arnold, Hugh, Chasse, Dawn, Monteith, Teresa, Ivaldi, Giovanni, Hahn, William C., Stukenberg, P. Todd +6 more·2004·Nature Cell Biology

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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Crossref · 10.1038/ncb1110

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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
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
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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