The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling
Open accessAbstract
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 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
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“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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Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
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Metadata
- 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
- 13
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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