Oncogenic ras and p53 Cooperate To Induce Cellular Senescence
Open accessAbstract
Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mouse, but not human, p19ARF is upregulated by various oncogenes (e.g., Ras and E2F), leading to p53 activation and senescence.
“Notably, mouse, but not human, p19ARF is upregulated by various oncogenes (e.g., Ras and E2F), leading to p53 activation and senescence [125,126].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 10× · see citing works
“phenotypically similar to replicative senescence (27, 49).”
BackgroundMethodInfluentialSelf-citationKastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047 · see citing works
Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81400-2 · Cited by 1,521 · see citing works
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · see citing works
Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization
Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F. (1998) · Genes & Development · doi:10.1101/gad.12.15.2424 · Cited by 1,245 · see citing works
Agarwal, M. L., Agarwal, A., Taylor, W. R., & Stark, G. R. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.18.8493 · Cited by 858 · see citing works
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745 · see citing works
Opposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357 · see citing works
Flagged first, then by citations
Research works printed but not linked: 10
- [7]7. Dimri, G. P., X. Lee, G. Basile, M. Acosta, G. Scott, C. Roskelley, E. E. Medrano, M. Linskens, I. Rubelj, O. Pereira-Smith, M. Peacocke, and J. Campisi. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 92: 9363-9367.
- [12]12. Ginsberg, D., F. Mechta, M. Yaniv, and M. Oren. 1991. Wild-type p53 can down-modulate the activity of various promoters. Proc. Natl. Acad. Sci. USA 88: 9979-9983.
- [20]20. Hollenberg, S. M., P. F. Cheng, and H. Weintraub. 1993. Use of a conditional MyoD transcription factor in studies of MyoD trans-activation and muscle determination. Proc. Natl. Acad. Sci. USA 90: 8028-8032.
- [22]22. Kapoor, M., and G. Lozano. 1998. Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc. Natl. Acad. Sci. USA 95: 2834-2837.
- [28]28. Lin, A. W., and S. W. Lowe. 2001. Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proc. Natl. Acad. Sci. USA 98: 5025-5030.
- [33]33. Lu, H., Y. Taya, M. Ikeda, and A. J. Levine. 1998. Ultraviolet radiation, but not gamma radiation or etoposide-induced DNA damage, results in the phosphorylation of the murine p53 protein at serine-389. Proc. Natl. Acad. Sci. USA 95: 6399-6402.
- [43]43. Pearson, M., R. Carbone, C. Sebastiani, M. Cioce, M. Fagioli, S. Saito, Y. Higashimoto, E. Appella, S. Minucci, P. P. Pandolfi, and P. G. Pelicci. 2000. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406: 207-210.
- [53]53. Sugrue, M. M., D. Y. Shin, S. W. Lee, and S. A. Aaronson. 1997. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc. Natl. Acad. Sci. USA 94: 9648-9653.
- [55]55. Tao, W., and A. J. Levine. 1999. P19(ARF) stabilizes p53 by blocking nucleocytoplasmic shuttling of Mdm2. Proc. Natl. Acad. Sci. USA 96: 6937-6941.
- [61]61. Wu, X., and A. J. Levine. 1994. p53 and E2F-1 cooperate to mediate apoptosis. Proc. Natl. Acad. Sci. USA 91: 3602-3606.
Cited by
Sorted by citations
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · see citing works
Self-citationThe RB and p53 pathways in cancer
Sherr, C. J., & McCormick, F. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00102-2 · Cited by 1,690 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy
Schmitt, C. A., Fridman, J. S., Yang, M., Lee, S., Baranov, E., Hoffman, R. M., & Lowe, S. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00734-1 · Cited by 1,050 · see citing works
Self-citationDNA damage response and cellular senescence in tissues of aging mice
Wang, C., Jurk, D., Maddick, M., Nelson, G., Martin‐Ruiz, C., & Von Zglinicki, T. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00481.x · Cited by 696 · see citing works
Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice
Kong, X., Feng, D., Wang, H., Hong, F., Bertola, A., Wang, F.-S., & Gao, B. (2012) · Hepatology · doi:10.1002/hep.25744 · Cited by 448 · see citing works
Human cell senescence as a DNA damage response
Zglinicki, T. V., Saretzki, G., Ladhoff, J., Fagagna, F. D. D., & Jackson, S. P. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.09.034 · Cited by 419 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence
Mallette, F. A., Gaumont-Leclerc, M.-F., & Ferbeyre, G. (2007) · Genes & Development · doi:10.1101/gad.1487307 · Cited by 406 · see citing works
Self-citationPML Is a Direct p53 Target that Modulates p53 Effector Functions
de Stanchina, E., Querido, E., Narita, M., Davuluri, R. V., Pandolfi, P. P., Ferbeyre, G., & Lowe, S. W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00062-0 · Cited by 312 · see citing works
Self-citationAstle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D., & Pearson, R. B. (2012) · Oncogene · doi:10.1038/onc.2011.394 · Cited by 295 · see citing works
The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.
Korotchkina, L. G., Leontieva, O. V., Bukreeva, E. I., Demidenko, Z. N., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100160 · Cited by 278 · see citing works
Paradoxical suppression of cellular senescence by p53
Demidenko, Z. N., Korotchkina, L. G., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002298107 · Cited by 273 · see citing works
Chan, I. T., Kutok, J. L., Williams, I. R., Cohen, S., Kelly, L., Shigematsu, H., Johnson, L., Akashi, K., Tuveson, D. A., Jacks, T., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20476 · Cited by 270 · see citing works
Cellular senescence and cancer treatment
Schmitt, C. A. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2006.08.005 · Cited by 254 · see citing works
DNA Damage Signaling and p53-dependent Senescence after Prolonged β-Interferon Stimulation
Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A., & Ferbeyre, G. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-09-0858 · Cited by 252 · see citing works
Self-citationKim, K. S., Seu, Y. B., Baek, S.-H., Kim, M. J., Kim, K. J., Kim, J. H., & Kim, J.-R. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-03-0280 · Cited by 199 · see citing works
Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
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., et al. (2013) · Genes & Development · doi:10.1101/gad.203984.112 · Cited by 194 · see citing works
Self-citationBulavin, D. V., Kovalsky, O., Hollander, M. C., & Fornace, A. J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.11.3859-3871.2003 · Cited by 161 · see citing works
Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression
Crose, L. E. S., Galindo, K. A., Kephart, J. G., Chen, C., Fitamant, J., Bardeesy, N., Bentley, R. C., Galindo, R. L., Ashley Chi, J.-T., & Linardic, C. M. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67087 · Cited by 124 · see citing works
Cellular lifespan and senescence signaling in embryonic stem cells
Miura, T., Mattson, M. P., & Rao, M. S. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00134.x · Cited by 102 · see citing works
Lysosomal trapping of palbociclib and its functional implications
Llanos, S., Megias, D., Blanco-Aparicio, C., Hernández-Encinas, E., Rovira, M., Pietrocola, F., & Serrano, M. (2019) · Oncogene · doi:10.1038/s41388-019-0695-8 · Cited by 96 · see citing works
Park, H., Kim, C.-H., Jeong, J.-H., Park, M., & Kim, K. S. (2016) · Oncotarget · doi:10.18632/oncotarget.7457 · Cited by 92 · see citing works
Mitochondrial DNA damage induces apoptosis in senescent cells
Laberge, R.-M., Adler, D., DeMaria, M., Mechtouf, N., Teachenor, R., Cardin, G. B., Desprez, P.-Y., Campisi, J., & Rodier, F. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.199 · Cited by 82 · see citing works
ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein
Boulay, P.-L., Schlienger, S., Lewis-Saravalli, S., Vitale, N., Ferbeyre, G., & Claing, A. (2011) · Oncogene · doi:10.1038/onc.2011.100 · Cited by 61 · see citing works
Self-citationAlcalde-Estévez, E., Asenjo-Bueno, A., Sosa, P., Olmos, G., Plaza, P., Caballero-Mora, M. Á., Rodríguez-Puyol, D., Ruíz-Torres, M. P., & López-Ongil, S. (2020) · Aging · doi:10.18632/aging.103450 · Cited by 35 · see citing works
Armeni, T., Ercolani, L., Urbanelli, L., Magini, A., Magherini, F., Pugnaloni, A., Piva, F., Modesti, A., Emiliani, C., & Principato, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052151 · Cited by 28 · see citing works
p73 cooperates with Ras in the activation of MAP kinase signaling cascade
Fernandez-Garcia, B., Vaqué, J. P., Herreros-Villanueva, M., Marques-Garcia, F., Castrillo, F., Fernandez-Medarde, A., León, J., & Marín, M. C. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401945 · Cited by 25 · see citing works
- Authors
- Ferbeyre, G., de Stanchina, E., Lin, A. W., Querido, E., McCurrach, M. E., Hannon, G. J., & Lowe, S. W.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Cold Spring Harbor Laboratory
- Corresponding author
- Lowe, Scott W.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-05
- Volume
- 22
- Issue
- 10
- Pages
- 3497-3508
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC133786
- OpenAlex
- W2098810873
- Cited by
- 290
- References
- 8
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 5 · 2023: 2 · 2022: 7 · 2021: 10 · 2020: 6 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 12 · 2015: 11 · 2014: 14 · 2013: 15 · 2012: 12
- FWCI
- 10.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute on Aging (R56AG016379, AG-16379, R01AG016379)
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, oncogenic Ras, p53, MAPK signaling, MEK1, cell cycle arrest, p53 stabilization, MDM2, tumor suppressor cooperation, mouse embryonic fibroblasts
- MeSH terms
- Animals, Cell Cycle, Cell Fractionation, Cells, Cultured, Colony-Forming Units Assay, Embryo, Mammalian, Enzyme Activation, Fibroblasts, Microscopy, Fluorescence, Nuclear Proteins, Proto-Oncogene Proteins, Genes, ras, Temperature, Genes, p53, Tumor Suppressor Protein p53, Cellular Senescence, Protein Serine-Threonine Kinases, Mice, Knockout, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Tumor Suppressor Protein p14ARF, MAP Kinase Kinase 1, Mice, Proto-Oncogene Proteins c-mdm2
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
