Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras -Induced Premature Senescence
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In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.
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Many factors in the tumor microenvironment, including cAMP, glucose competition, and oncogenic stress, can induce senescence of T cells, macrophages, natural killer cells, and dendritic cells.
“The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [59]
Tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells.
“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [59]
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Background
- Authors
- Wang, W., Chen, J. X., Liao, R., Deng, Q., Zhou, J. J., Huang, S., & Sun, P.
- Affiliations
- Department of Molecular Biology
- Scripps Research Institute (US)
- Corresponding author
- Sun, Peiqing
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-05-01
- Volume
- 22
- Issue
- 10
- Pages
- 3389-3403
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC133789
- OpenAlex
- W2168395104
- Cited by
- 376
- References
- 64
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 13 · 2023: 6 · 2022: 11 · 2021: 7 · 2020: 16 · 2019: 19 · 2018: 15 · 2017: 7 · 2016: 13 · 2015: 13 · 2014: 21 · 2013: 18 · 2012: 29
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Ellison Medical Foundation
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- oncogenic Ras, premature senescence, MEK/ERK signaling, p38 MAPK, MKK3, MKK6, MEK1, MAPK signaling, primary human fibroblasts, oncogenic transformation, growth inhibition
- MeSH terms
- Cells, Cultured, Enzyme Activation, Fibroblasts, Humans, Protein-Tyrosine Kinases, Genes, ras, Tumor Necrosis Factor-alpha, Cellular Senescence, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Cyclin-Dependent Kinase Inhibitor p16, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 3, Cell Size, MAP Kinase Kinase 6, MAP Kinase Kinase Kinase 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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