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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
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 5,218 · cited 24×
“7; see also Serrano et al. 1997).”
BackgroundMethodInfluentialSelf-citationMice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Butel, J. S., & Bradley, A. (1992) · Nature · doi:10.1038/356215a0 · Cited by 4,649
Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours
Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., & Giaccia, A. J. (1996) · Nature · doi:10.1038/379088a0 · Cited by 2,300
Self-citationPhosphatidylinositol-3-OH kinase direct target of Ras
Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., & Downward, J. (1994) · Nature · doi:10.1038/370527a0 · Cited by 1,954
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566
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
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., & Barrett, J. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13742 · Cited by 1,008
Zindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574
Tanaka, N., Ishihara, M., Kitagawa, M., Harada, H., Kimura, T., Matsuyama, T., Lamphier, M. S., Aizawa, S., Mak, T. W., & Taniguchi, T. (1994) · Cell · doi:10.1016/0092-8674(94)90132-5 · Cited by 491
McConnell, B. B., Starborg, M., Brookes, S., & Peters, G. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70137-x · Cited by 314 · cited 3×
“Consistent with this view, ectopic expression of p21 (a p53 target) and p16 can induce senescence in human cells (McConnell et al. 1998; Vogt et al. 1998).”
BackgroundIncreased activity of p53 in senescing fibroblasts
Atadja, P., Wong, H., Garkavtsev, I., Veillette, C., & Riabowol, K. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.18.8348 · Cited by 308
Ogryzko, V. V., Hirai, T. H., Russanova, V. R., Barbie, D. A., & Howard, B. H. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.5210 · Cited by 268
Franza, B. R., Maruyama, K., Garrels, J. I., & Ruley, H. E. (1986) · Cell · doi:10.1016/0092-8674(86)90462-9 · Cited by 166
Research works printed but not linked: 67
- 10.1074/jbc.270.46.27489 · DOI
- 10.1016/0092-8674(93)90663-B · DOI
- Bottorff, 1995, RAS signalling is abnormal in a c-raf1 MEK1 double mutant., Mol. Cell. Biol., 15, 5113, 10.1128/MCB.15.9.5113 · DOI
- Burns, 1991, Loss of heterozygosity and mutational alterations of the p53 gene in skin tumours of interspecific hybrid mice., Oncogene, 6, 2363
- Chen, 1992, Nuclear localization and regulation of erk- and rsk-encoded protein kinases., Mol. Cell. Biol., 12, 915
- 10.1101/gad.11.21.2822 · DOI
- 10.1016/0092-8674(94)90133-3 · DOI
- 10.1101/gad.12.15.2434 · DOI
- 10.1073/pnas.92.20.9363 · DOI · Paper page
- 10.1016/S0959-437X(98)80061-0 · DOI
- 10.1073/pnas.92.17.7686 · DOI
- 10.1016/0092-8674(92)90123-T · DOI
- 10.1016/0092-8674(90)90186-I · DOI · Paper page
- Foster, 1998, Inactivation of p16 in human mammary epithelial cells by CpG island methylation., Mol. Cell. Biol., 18, 1793, 10.1128/MCB.18.4.1793 · DOI
- Fukasawa, 1997, Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability., Mol. Cell. Biol., 17, 506, 10.1128/MCB.17.1.506 · DOI
- Gallimore, 1986, Transformation of human embryo retinoblasts with simian virus 40, adenovirus and ras oncogenes., Anticancer Res., 6, 499
- Gille, 1995, ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation., EMBO J., 14, 951, 10.1002/j.1460-2075.1995.tb07076.x · DOI
- Graham, 1996, TC21 causes transformation by Raf-independent signaling pathways., Mol. Cell. Biol., 16, 6132, 10.1128/MCB.16.11.6132 · DOI
- 10.1016/S0960-9822(98)70105-8 · DOI · Paper page
- 10.1016/S0092-8674(00)80441-9 · DOI
- 10.1016/0014-4827(65)90211-9 · DOI · Paper page
- 10.1073/pnas.85.5.1519 · DOI
- 10.1016/0014-4827(86)90499-4 · DOI
- 10.1016/S0960-9822(00)00002-6 · DOI · Paper page
- 10.1038/378409a0 · DOI
- 10.1126/science.271.5250.810 · DOI
- Kastan, 1993, P53: A determinant of the cell cycle response to DNA damage., Adv. Exp. Med. Biol., 339, 291, 10.1007/978-1-4615-2488-5_28 · DOI
- 10.1016/S0959-437X(97)80112-8 · DOI
- 10.1016/0092-8674(93)90461-X · DOI
- Kerkhoff, 1998, High-intensity Raf signals convert mitotic cell cycling into cellular growth., Cancer Res., 58, 1636
- Khosravi-Far, 1995, Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation., Mol. Cell. Biol., 15, 6443, 10.1128/MCB.15.11.6443 · DOI · Paper page
- Linardopoulos, 1995, Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors., Cancer Res., 55, 5168
- Linke, 1997, p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation., Cancer Res., 57, 1171
- Lumpkin, 1986, Mitogenic effects of the proto-oncogene and oncogene forms of c-H-ras DNA in human diploid fibroblasts., Mol. Cell. Biol., 6, 2990
- 10.1126/science.8052857 · DOI
- 10.1016/0959-437X(94)90095-7 · DOI
- 10.1038/33293 · DOI
- 10.1016/S0960-9822(06)00028-5 · DOI · Paper page
- 10.1093/nar/18.12.3587 · DOI
- 10.1006/excr.1994.1063 · DOI · Paper page
- 10.1038/28425 · DOI
- 10.1038/sj.onc.1201212 · DOI
- 10.1038/25870 · DOI
- 10.1073/pnas.94.2.448 · DOI
- 10.1016/0092-8674(95)90214-7 · DOI · Paper page
- Reznikoff, 1996, Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells., Cancer Res., 56, 2886
- 10.1016/S0092-8674(00)80226-3 · DOI
- Ruley, 1990, Transforming collaborations between ras and nuclear oncogenes., Cancer Cells, 2, 258
- 10.1073/pnas.94.22.12094 · DOI
- 10.1016/S0092-8674(00)81079-X · DOI · Paper page
- Sewing, 1997, High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1., Mol. Cell. Biol., 17, 5588, 10.1128/MCB.17.9.5588 · DOI
- 10.1073/pnas.91.26.12609 · DOI
- Stang, 1997, Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of rat2 cells., Mol. Cell. Biol., 17, 3047, 10.1128/MCB.17.6.3047 · DOI
- 10.1038/sj.onc.1201227 · DOI
- Urano, 1996, Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation., EMBO J., 15, 810, 10.1002/j.1460-2075.1996.tb00416.x · DOI
- 10.1101/gad.11.18.2295 · DOI
- 10.1073/pnas.90.13.6213 · DOI
- 10.1074/jbc.270.51.30701 · DOI
- Vogt, 1998, Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts., Cell Growth Differ., 9, 139
- Vojta, 1995, Genetic analysis of cellular senescence., Biochim. Biophys. Acta, 1242, 29
- Weinberg, 1989, Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis., Cancer Res., 49, 3713
- 10.1016/S0092-8674(00)81897-8 · DOI
- 10.1016/0092-8674(95)90507-3 · DOI
- 10.1016/0531-5565(90)90040-9 · DOI
- 10.1126/science.7652577 · DOI
- Woods, 1997, Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1., Mol. Cell. Biol., 17, 5598, 10.1128/MCB.17.9.5598 · DOI
- Zhu, J., D. Woods, M. McMahon, and J.M. Bishop. 1998. Senescence of human fibroblasts induced by oncogenic Raf. Genes & Dev. (this issue).. · DOI · Paper page
Cited by
Sorted by citations
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
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
Self-citationBRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986
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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