Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling
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Oncogenic Ras transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Ras is initially mitogenic but eventually induces premature senescence involving the p53 and p16 INK4a tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a . The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.
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The initial response of normal cells to constitutively active oncogenic stimuli is typically hyperproliferation, which appears sensed by cells, triggering senescence.
“The initial response of normal cells to constitutively active oncogenic stimuli is typically hyperproliferation, which appears to be “sensed” by cells, triggering a senescence phenotype (Lin et al. 1998).”
From Cellular senescence and its effector programs (2014) · cites this paper as Lin et al. 1998
In “Oncogenic Ras is initially mitogenic in normal diploid human fibroblasts,” the paper reports that Ras first forces proliferation and only later produces a senescent phenotype. “Role of the MAPK cascade in cell-cycle arrest” describes senescence as a response to excessive MEK/MAPK activity. These passages support the sequence for Ras signaling, but not the broader assertion that normal cells typically respond this way to constitutively active oncogenic stimuli in general. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOIS was initially described in culture, where ectopic expression of oncogenic HRAS-G12V or its downstream effectors led to premature senescence.
“OIS was initially described in culture, where the ectopic expression of oncogenic HRAS-G12V, or its downstream effectors paradoxically led to premature senescence [19][20][21] .”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [20]
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- Authors
- Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., & Lowe, S. W.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- University of Alberta (CA)
- Corresponding author
- Lowe, Scott W.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-10-01
- Volume
- 12
- Issue
- 19
- Pages
- 3008-3019
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317198
- OpenAlex
- W2125547572
- Cited by
- 945
- References
- 9
- Citations by year
- 2026: 21 · 2025: 16 · 2024: 20 · 2023: 21 · 2022: 21 · 2021: 31 · 2020: 19 · 2019: 21 · 2018: 33 · 2017: 29 · 2016: 25 · 2015: 21 · 2014: 40 · 2013: 33 · 2012: 35
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca072982-04)
- National Cancer Institute (CA72982, CA13106, P01CA013106)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- premature senescence, p53, p16INK4a, MEK, MAPK signaling, Ras, mitogenic signaling, tumor suppressor, cell transformation, fibroblasts, cell cycle arrest, immortalized cells
- MeSH terms
- Animals, Cell Cycle, Cell Transformation, Neoplastic, Cells, Cultured, Fibroblasts, Humans, Microinjections, Protein-Tyrosine Kinases, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice
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