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

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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, Shenolikar, Shirish, Uchida, Takafumi, Counter, Christopher M., Nevins, Joseph R., Means, Anthony R., Sears, Rosalie·2004·Nature Cell Biology

DOI 10.1038/ncb1110

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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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Additional file 1 of The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Moser, B., Hochreiter, B., Basílio, J., Gleitsmann, V., Panhuber, A., Pardo-Garcia, A., Hoesel, B., Salzmann, M., Resch, U., Noreen, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13605686
Additional file 5 of Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth
Khan, S., Zuccato, J., Ignatchenko, V., Singh, O., Govindarajan, M., Waas, M., Mejia‐Guerrero, S., Gao, A., Zadeh, G., & Kislinger, T. (2024) · Figshare · doi:10.6084/m9.figshare.26690261
Additional file 4 of The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Moser, B., Hochreiter, B., Basílio, J., Gleitsmann, V., Panhuber, A., Pardo-Garcia, A., Hoesel, B., Salzmann, M., Resch, U., Noreen, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13605695
Additional file 2 of Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth
Khan, S., Zuccato, J., Ignatchenko, V., Singh, O., Govindarajan, M., Waas, M., Mejia‐Guerrero, S., Gao, A., Zadeh, G., & Kislinger, T. (2024) · Figshare · doi:10.6084/m9.figshare.26690252
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Additional file 1 of Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth
Khan, S., Zuccato, J., Ignatchenko, V., Singh, O., Govindarajan, M., Waas, M., Mejia‐Guerrero, S., Gao, A., Zadeh, G., & Kislinger, T. (2024) · Figshare · doi:10.6084/m9.figshare.26690249
Additional file 3 of Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth
Khan, S., Zuccato, J., Ignatchenko, V., Singh, O., Govindarajan, M., Waas, M., Mejia‐Guerrero, S., Gao, A., Zadeh, G., & Kislinger, T. (2024) · Figshare · doi:10.6084/m9.figshare.26690255
Additional file 2 of The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Moser, B., Hochreiter, B., Basílio, J., Gleitsmann, V., Panhuber, A., Pardo-Garcia, A., Hoesel, B., Salzmann, M., Resch, U., Noreen, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13605689
Additional file 4 of Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth
Khan, S., Zuccato, J., Ignatchenko, V., Singh, O., Govindarajan, M., Waas, M., Mejia‐Guerrero, S., Gao, A., Zadeh, G., & Kislinger, T. (2024) · Figshare · doi:10.6084/m9.figshare.26690258
Additional file 3 of The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Moser, B., Hochreiter, B., Basílio, J., Gleitsmann, V., Panhuber, A., Pardo-Garcia, A., Hoesel, B., Salzmann, M., Resch, U., Noreen, M., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13605692
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Chemical Induction of MYC Protein Degradation via MYC–MAX Disruption and 20S Proteasome Activation
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BindingDB Entry 50004347: Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1.
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BindingDB Entry 50038049: A phosphorylated prodrug for the inhibition of Pin1.
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MYC-induced lymphomagenesis Inhibition of HMGcoA reductase by atorvastatin prevents and reverses
Steinman, L., Felsher, D. W., Sharpe, O., Chen, J., Mitchell, D. J., Chang, M., Nolan, G. P., Shachaf, C. M., Perez, O. D., Youssef, S., et al. (2013)

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: Yeh, Elizabeth
Chasse, Dawn
Hahn, William C.
Stukenberg, P. Todd
Shenolikar, Shirish
Uchida, Takafumi
Counter, Christopher M.
Means, Anthony R.
Sears, Rosalie
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2004-03-14
Volume: 6
Issue: 4
Pages: 308-318
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb1110
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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A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells

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