Senescence of human fibroblasts induced by oncogenic Raf
Open accessAbstract
The oncogenes RAS and RAF came to view as agents of neoplastic transformation. However, in normal cells, these genes can have effects that run counter to oncogenic transformation, such as arrest of the cell division cycle, induction of cell differentiation, and apoptosis. Recent work has demonstrated that RAS elicits proliferative arrest and senescence in normal mouse and human fibroblasts. Because the Raf/MEK/MAP kinase signaling cascade is a key effector of signaling from Ras proteins, we examined the ability of conditionally active forms of Raf-1 to elicit cell cycle arrest and senescence in human cells. Activation of Raf-1 in nonimmortalized human lung fibroblasts (IMR-90) led to the prompt and irreversible arrest of cellular proliferation and the premature onset of senescence. Concomitant with the onset of cell cycle arrest, we observed the induction of the cyclin-dependent kinase (CDK) inhibitors p21 Cip1 and p16 Ink4a. Ablation of p53 and p21 Cip1 expression by use of the E6 oncoprotein of HPV16 demonstrated that expression of these proteins was not required for Raf-induced cell cycle arrest or senescence. Furthermore, cell cycle arrest and senescence were elicited in IMR-90 cells by the ectopic expression of p16 Ink4a alone. Pharmacological inhibition of the Raf/MEK/MAP kinase cascade prevented Raf from inducing p16 Ink4a and also prevented Raf-induced senescence. We conclude that the kinase cascade initiated by Raf can regulate the expression of p16 Ink4a and the proliferative arrest and senescence that follows. Induction of senescence may provide a defense against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.
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OIS 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 [21]
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- Authors
- Zhu, J., Woods, D., McMahon, M., & Bishop, J. M.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-10-01
- Volume
- 12
- Issue
- 19
- Pages
- 2997-3007
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317194
- OpenAlex
- W1966453709
- Cited by
- 826
- References
- 11
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 10 · 2023: 18 · 2022: 18 · 2021: 16 · 2020: 16 · 2019: 18 · 2018: 19 · 2017: 16 · 2016: 29 · 2015: 20 · 2014: 39 · 2013: 31 · 2012: 33
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 44338-12, R35CA044338)
- 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
- cellular senescence, Raf-1, cell cycle arrest, p16INK4a, p21, cyclin-dependent kinase inhibitors, p53, HPV16 E6, oncogenic transformation, proliferative arrest
- MeSH terms
- Animals, beta-Galactosidase, Cell Division, Cells, Cultured, Fibroblasts, Humans, Signal Transduction, Tumor Suppressor Protein p53, Cyclins, Cellular Senescence, Calcium-Calmodulin-Dependent Protein Kinases, ras Proteins, Cell Cycle Proteins, Proto-Oncogene Proteins c-raf, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Mice
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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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