Cited by 194Telomeres, Telomerase, and SenescenceMelanoma and MAPK PathwaysGenetics, Aging, and Longevity in Model Organisms

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Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

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Deschênes-Simard, Xavier, Gaumont-Leclerc, Marie-France, Bourdeau, Véronique, Lessard, Frédéric, Moiseeva, Olga, Forest, Valérie, Igelmann, Sebastian, Mallette, Frédérick A., Saba-El-Leil, Marc K., Meloche, Sylvain, Saad, Fred, Mes-Masson, Anne-Marie, Ferbeyre, Gerardo·2013·Genes & Development

DOI 10.1101/gad.203984.112PMC PMC3650227

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Abstract

Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. In primary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAP kinase signaling by genetic inactivation of Erk2, RNAi-mediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented the activation of the senescence mechanism, allowing oncogenic ras to transform primary cells. Mechanistically, ERK-mediated senescence involved the proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions, cell migration, RNA metabolism, and cell signaling. This senescence-associated protein degradation (SAPD) was observed not only in cells expressing ectopic ras , but also in cells that senesced due to short telomeres. Individual RNAi-mediated inactivation of SAPD targets was sufficient to restore senescence in cells transformed by oncogenic ras or trigger senescence in normal cells. Conversely, the anti-senescence viral oncoproteins E1A, E6, and E7 prevented SAPD. In human prostate neoplasms, high levels of phosphorylated ERK were found in benign lesions, correlating with other senescence markers and low levels of STAT3, one of the SAPD targets. We thus identified a mechanism that links aberrant activation of growth signaling pathways and short telomeres to protein degradation and cellular senescence.

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Authors: Deschênes-Simard, X., Gaumont-Leclerc, M.-F., Bourdeau, V., Lessard, F., Moiseeva, O., Forest, V., Igelmann, S., Mallette, F. A., Saba-El-Leil, M. K., Meloche, S., Saad, F., Mes-Masson, A.-M., & Ferbeyre, G.
Affiliations: Université de Montréal (CA)
Centre Hospitalier de l’Université de Montréal (CA)
Institute for Research in Immunology and Cancer (CA)
ORCID: Bourdeau, Véronique
Lessard, Frédéric
Moiseeva, Olga
Forest, Valérie
Igelmann, Sebastian
Mallette, Frédérick A.
Meloche, Sylvain
Ferbeyre, Gerardo
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2013-04-15
Volume: 27
Issue: 8
Pages: 900-915
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.203984.112
PMC: PMC3650227
OpenAlex: W1978818809
Cited by: 194
References: 60
Citations by year: 2026: 4 · 2025: 14 · 2024: 7 · 2023: 19 · 2022: 16 · 2021: 19 · 2020: 18 · 2019: 19 · 2018: 19 · 2017: 14 · 2016: 13 · 2015: 9 · 2014: 16 · 2013: 7
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: cellular senescence, ERK signaling, oncogenic Ras, protein degradation, short telomeres, tumor suppressor activity, MEK inhibitors, STAT3, viral oncoproteins, prostate cancer, proteasome
MeSH terms: Animals, Cell Line, Cell Transformation, Neoplastic, Female, Fibroblasts, Humans, Male, Mice, Inbred BALB C, Prostatic Neoplasms, Cellular Senescence, Mice, Knockout, ras Proteins, MAP Kinase Signaling System, Tumor Suppressor Proteins, Proteasome Endopeptidase Complex, Mice, Gene Knockdown Techniques, Proteolysis

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Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

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