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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).”
Background
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
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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
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Self-citationFour faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,070
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence
Cagnol, S., & Chambard, J. (2010) · The FEBS Journal · doi:10.1111/j.1742-4658.2009.07366.x · Cited by 1,290
Oncogene-induced senescence as an initial barrier in lymphoma development
Braig, M., Lee, S., Loddenkemper, C., Rudolph, C., Peters, A. H. F. M., Schlegelberger, B., Stein, H., Dörken, B., Jenuwein, T., & Schmitt, C. A. (2005) · Nature · doi:10.1038/nature03841 · Cited by 1,220
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
Senescence-associated reprogramming promotes cancer stemness
Milanovic, M., Fan, D. N. Y., Belenki, D., Däbritz, J. H. M., Zhao, Z., Yu, Y., Dörr, J. R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I. A., et al. (2018) · Nature · doi:10.1038/nature25167 · Cited by 1,131
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124
Self-citationMeloche, S., & Pouysségur, J. (2007) · Oncogene · doi:10.1038/sj.onc.1210414 · Cited by 1,091
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., et al. (2011) · Genes & Development · doi:10.1101/gad.17276711 · Cited by 1,046
Self-citationThe senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855
Cellular senescence and tumor suppressor gene p16
Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012) · International Journal of Cancer · doi:10.1002/ijc.27316 · Cited by 825
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798
Microarray analysis of replicative senescence
Shelton, D. N., Chang, E., Whittier, P. S., Choi, D., & Funk, W. D. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80420-5 · Cited by 764
DNA 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
Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence
Ohtani, N., Zebedee, Z., Huot, T. J. G., Stinson, J. A., Sugimoto, M., Ohashi, Y., Sharrocks, A. D., Peters, G., & Hara, E. (2001) · Nature · doi:10.1038/35059131 · Cited by 654
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109745200 · Cited by 617
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588
The Differential Effects of Mutant p53 Alleles on Advanced Murine Lung Cancer
Jackson, E. L., Olive, K. P., Tuveson, D. A., Bronson, R., Crowley, D., Brown, M., & Jacks, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2193 · Cited by 553
Aging and Genome Maintenance: Lessons from the Mouse?
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., & Vijg, J. (2003) · Science · doi:10.1126/science.1079161 · Cited by 553
PML is induced by oncogenic ras and promotes premature senescence
Ferbeyre, G., de Stanchina, E., Querido, E., Baptiste, N., Prives, C., & Lowe, S. W. (2000) · Genes & Development · doi:10.1101/gad.14.16.2015 · Cited by 536
Self-citationThe INK4A/ARF locus and its two gene products.
Sharpless, N. E., & DePinho, R. A. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80004-5 · Cited by 533
twist is a potential oncogene that inhibits apoptosis
Maestro, R., Tos, A. P. D., Hamamori, Y., Krasnokutsky, S., Sartorelli, V., Kedes, L., Doglioni, C., Beach, D. H., & Hannon, G. J. (1999) · Genes & Development · doi:10.1101/gad.13.17.2207 · Cited by 516
Inside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462
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
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Serrano, M., & Blasco, M. A. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00278-7 · Cited by 413
Self-citationMitochondrial Dysfunction Contributes to Oncogene-Induced Senescence
Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., & Ferbeyre, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01868-08 · Cited by 408
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J., Egia, A., Nakayama, K. I., et al. (2010) · Nature · doi:10.1038/nature08815 · Cited by 400
Cellular senescence as a tumor-suppressor mechanism
Campisi, J. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)82148-6 · Cited by 390
Tumor suppressors and oncogenes in cellular senescence
Bringold, F., & Serrano, M. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(00)00083-8 · Cited by 379
Self-citationWang, W., Chen, J. X., Liao, R., Deng, Q., Zhou, J. J., Huang, S., & Sun, P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.10.3389-3403.2002 · Cited by 376
Global reorganization of the nuclear landscape in senescent cells
Chandra, T., Ewels, P. A., Schoenfelder, S., Furlan-Magaril, M., Wingett, S. W., Kirschner, K., Thuret, J.-Y., Andrews, S., Fraser, P., & Reik, W. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.055 · Cited by 348
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Greenberg, R. A., Chin, L., Femino, A., Lee, K.-H., Gottlieb, G. J., Singer, R. H., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80761-8 · Cited by 367
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Itahana, K., Dimri, G., & Campisi, J. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02228.x · Cited by 365
Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., Rydkina, E., Vujcic, S., Balan, K., Gitlin, I., et al. (2016) · Aging · doi:10.18632/aging.100991 · Cited by 357
Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival
Drosten, M., Dhawahir, A., Sum, E. Y. M., Urosevic, J., Lechuga, C. G., Esteban, L. M., Castellano, E., Guerra, C., Santos, E., & Barbacid, M. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.7 · Cited by 347
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
Denoyelle, C., Abou-Rjaily, G., Bezrookove, V., Verhaegen, M., Johnson, T. M., Fullen, D. R., Pointer, J. N., Gruber, S. B., Su, L. D., Nikiforov, M. A., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1471 · Cited by 349
Mitochondrial dysfunction and cell senescence: deciphering a complex relationship
Chapman, J., Fielder, E., & Passos, J. F. (2019) · FEBS Letters · doi:10.1002/1873-3468.13498 · Cited by 325
Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence
Adams, P. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.021 · Cited by 326
Genes involved in senescence and immortalization
Lundberg, A. S., Hahn, W. C., Gupta, P., & Weinberg, R. A. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00155-1 · Cited by 313
PML 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
Self-citationCigarette smoke induces cellular senescence
Nyunoya, T., Monick, M. M., Klingelhutz, A., Yarovinsky, T. O., Cagley, J. R., & Hunninghake, G. W. (2006) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2006-0169oc · Cited by 306
Cao, L., Li, W., Kim, S., Brodie, S. G., & Deng, C.-X. (2003) · Genes & Development · doi:10.1101/gad.1050003 · Cited by 293
Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence
Xu, Y., Li, N., Xiang, R., & Sun, P. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.04.004 · Cited by 282
Weyemi, U., Lagente-Chevallier, O., Boufraqech, M., Prenois, F., Courtin, F., Caillou, B., Talbot, M., Dardalhon, M., Al Ghuzlan, A., Bidart, J.-M., et al. (2012) · Oncogene · doi:10.1038/onc.2011.327 · Cited by 285
The p16INK4a-RB pathway : molecular link between cellular senescence and tumor suppression
Ohtani, N., Yamakoshi, K., Takahashi, A., & Hara, E. (2004) · The Journal of Medical Investigation · doi:10.2152/jmi.51.146 · Cited by 276
Oncogene-Induced Senescence: Putting the Brakes on Tumor Development
Braig, M., & Schmitt, C. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4006 · Cited by 274
Cellular senescence in vivo: a barrier to tumorigenesis
Prieur, A., & Peeper, D. S. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.01.007 · Cited by 260
Oncogene-induced senescence: the bright and dark side of the response
Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.07.013 · Cited by 257
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
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
Blagosklonny, M. V. (2012) · Aging · doi:10.18632/aging.100443 · Cited by 251
Ageing: from inflammation to cancer
Leonardi, G. C., Accardi, G., Monastero, R., Nicoletti, F., & Libra, M. (2018) · Immunity & Ageing · doi:10.1186/s12979-017-0112-5 · Cited by 241
Role of p14ARF in Replicative and Induced Senescence of Human Fibroblasts
Wei, W., Hemmer, R. M., & Sedivy, J. M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.20.6748-6757.2001 · Cited by 217
Kennedy, A. L., Morton, J. P., Manoharan, I., Nelson, D. M., Jamieson, N. B., Pawlikowski, J. S., McBryan, T., Doyle, B., McKay, C., Oien, K. A., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.020 · Cited by 213
Pantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201
Senescent Cardiac Fibroblast Is Critical for Cardiac Fibrosis after Myocardial Infarction
Zhu, F., Li, Y., Zhang, J., Piao, C., Liu, T., Li, H.-H., & Du, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074535 · Cited by 201
Genetic and Epigenetic Changes in Human Epithelial Cells Immortalized by Telomerase
Farwell, D. G., Shera, K. A., Koop, J. I., Bonnet, G. A., Matthews, C. P., Reuther, G. W., Coltrera, M. D., McDougall, J. K., & Klingelhutz, A. J. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65025-0 · Cited by 196
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
Assessing cell and organ senescence biomarkers
de Jesus, B. B., & Blasco, M. A. (2012) · Circulation Research · doi:10.1161/circresaha.111.247866 · Cited by 187
Stable Cellular Senescence Is Associated with Persistent DDR Activation
Fumagalli, M., Rossiello, F., Mondello, C., & d’Adda di Fagagna, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110969 · Cited by 183
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53
Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200904105 · Cited by 172
Requirement for p27KIP1 in Retinoblastoma Protein-Mediated Senescence
Alexander, K., & Hinds, P. W. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.11.3616-3631.2001 · Cited by 164
Yokoi, T., Fukuo, K., Yasuda, O., Hotta, M., Miyazaki, J., Takemura, Y., Kawamoto, H., Ichijo, H., & Ogihara, T. (2006) · Diabetes · doi:10.2337/db05-1607 · Cited by 169
Tang, Y., Horikawa, I., Ajiro, M., Robles, A. I., Fujita, K., Mondal, A. M., Stauffer, J. K., Zheng, Z.-M., & Harris, C. C. (2013) · Oncogene · doi:10.1038/onc.2012.288 · Cited by 165
Bulavin, 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
Cell senescence and hypermitogenic arrest
Blagosklonny, M. V. (2003) · The EMBO Reports · doi:10.1038/sj.embor.embor806 · Cited by 156
Insulin‐like growth factor‐1 regulates the SIRT 1‐p53 pathway in cellular senescence
Tran, D., Bergholz, J., Zhang, H., He, H., Wang, Y., Zhang, Y., Li, Q., Kirkland, J. L., & Xiao, Z. (2014) · Aging Cell · doi:10.1111/acel.12219 · Cited by 161
“Although initially mitogenic, hyperactivated Ras effectively promotes oncogene-induced cellular senescence at a later stage by inducing p16 as well as ARF, which inhibit MDM2, leading to increased p53 proteins levels (Lin et al., 1998).”
BackgroundInfluentialChen, H., Chen, H., Liang, J., Gu, X., Zhou, J., Xie, C., Lv, X., Wang, R., Li, Q., Mao, Z., et al. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0371-7 · Cited by 149
Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Yaeger, R., Mezzadra, R., Sinopoli, J., Bian, Y., Marasco, M., Kaplun, E., Gao, Y., Zhao, H., Paula, A. D. C., Zhu, Y., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0405 · Cited by 144
Self-citationInk4a/Arf links senescence and aging
Sharpless, N. E. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.06.025 · Cited by 142
Krizhanovsky, V., Xue, W., Zender, L., Yon, M., Hernando, E., & Lowe, S. W. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.048 · Cited by 138
Self-citationSprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
Shaw, A. T., Meissner, A., Dowdle, J. A., Crowley, D., Magendantz, M., Ouyang, C., Parisi, T., Rajagopal, J., Blank, L. J., Bronson, R. T., et al. (2007) · Genes & Development · doi:10.1101/gad.1526207 · Cited by 131
Self-citationMolecular signature of oncogenic ras-induced senescence
Mason, D. X., Jackson, T. J., & Lin, A. W. (2004) · Oncogene · doi:10.1038/sj.onc.1208172 · Cited by 127
Self-citationCellular senescence predicts treatment outcome in metastasised colorectal cancer
Haugstetter, A. M., Loddenkemper, C., Lenze, D., Gröne, J., Standfuß, C., Petersen, I., Dörken, B., & Schmitt, C. A. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605784 · Cited by 117
Oikawa, T., Yamada, T., Kihara-Negishi, F., Yamamoto, H., Kondoh, N., Hitomi, Y., & Hashimoto, Y. (1999) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4400534 · Cited by 109
Huot, T. J., Rowe, J., Harland, M., Drayton, S., Brookes, S., Gooptu, C., Purkis, P., Fried, M., Bataille, V., Hara, E., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.23.8135-8143.2002 · Cited by 107
Regulation of senescence and the SASP by the transcription factor C/EBPβ
Salotti, J., & Johnson, P. F. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110752 · Cited by 103
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
Conserved senescence associated genes and pathways in primary human fibroblasts detected by RNA-seq
Marthandan, S., Baumgart, M., Priebe, S., Groth, M., Schaer, J., Kaether, C., Guthke, R., Cellerino, A., Platzer, M., Diekmann, S., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0154531 · Cited by 91
Cellular senescence and tumor promotion: Is aging the key?
Loaiza, N., & Demaria, M. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.01.007 · Cited by 101
Zeng, X., & Rao, M. S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.09.017 · Cited by 92
Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence.
Lenain, C., de Graaf, C. A., Pagie, L., Visser, N. L., de Haas, M., de Vries, S. S., Peric-Hupkes, D., van Steensel, B., & Peeper, D. S. (2017) · Genome Research · doi:10.1101/gr.225763.117 · Cited by 89
Short-term gain, long-term pain: the senescence life cycle and cancer
Chan, A. S. L., & Narita, M. (2019) · Genes & Development · doi:10.1101/gad.320937.118 · Cited by 80
Non-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
Saleh, T., Tyutynuk-Massey, L., Cudjoe, E. K., Idowu, M. O., Landry, J. W., & Gewirtz, D. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00164 · Cited by 85
Detection of senescence using machine learning algorithms based on nuclear features
Duran, I., Pombo, J., Sun, B., Gallage, S., Kudo, H., McHugh, D., Bousset, L., Barragan Avila, J. E., Forlano, R., Manousou, P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45421-w · Cited by 85
Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., & Hara, E. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.006 · Cited by 84
Senescence in polyploid giant cancer cells: A road that leads to chemoresistance
Bharadwaj, D., & Mandal, M. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.11.002 · Cited by 64
Tabach, Y., Milyavsky, M., Shats, I., Brosh, R., Zuk, O., Yitzhaky, A., Mantovani, R., Domany, E., Rotter, V., & Pilpel, Y. (2005) · Molecular Systems Biology · doi:10.1038/msb4100030 · Cited by 72
Yang, X., He, Z., Xin, B., & Cao, L. (2000) · Oncogene · doi:10.1038/sj.onc.1203515 · Cited by 71
Markers of cellular senescence.
Carnero, A. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_4 · Cited by 68
Molecular pathology endpoints useful for aging studies
Niedernhofer, L. J., Kirkland, J. L., & Ladiges, W. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.012 · Cited by 59
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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