Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.

Pantoja, Cristina; Serrano, Manuel

doi:10.1038/sj.onc.1202880

Cited by 201Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenetics, Aging, and Longevity in Model Organisms

Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.

Pantoja, Cristina, Serrano, Manuel·1999·Oncogene

DOI 10.1038/sj.onc.1202880

Open this paper in CoChat — free account

Abstract

The cell-cycle inhibitor p21 is upregulated during senescence and upon induction of senescence-like arrest by oncogenic Ras. We have used primary fibroblasts derived from p21-null mice to evaluate the role of p21 in these processes. We find that primary p21-/- cells enter senescence and have a lifespan similar to wild-type cells. Upon immortalization, most wild-type and p21-/- cultures acquire alterations in either p53 or p16INK4a, further indicating that p21-deficiency is not sufficient by itself to allow immortalization. Primary p21-/- cells, like wild-type cells, respond to oncogenic Ras by accumulating p53 and p16INK4a, and by decreasing their proliferation rate. In agreement with this, p21-/- cells are refractory to neoplasic transformation by oncogenic Ras when compared to p53-/- cells. We conclude that, in murine fibroblasts, p21 is not essential neither for senescence nor for preventing neoplasic transformation by oncogenic Ras.

Integrity signals

Registry

Crossref · 10.1038/sj.onc.1202880

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

Increased expression of p21 also plays a role in induction of senescence, particularly during its initiation.
“Increased expression of p21 also plays a role in induction of senescence, particularly during its initiation.26”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [26]

WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Wade Harper, J. (1993) · Cell · doi:10.1016/0092-8674(93)90499-g · Cited by 5,651 · see citing works
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 14× · see citing works
“Accordingly, rodent cells de®cient in p53 or p16 are e ciently transformed by oncogenic Ras (Serrano et al., 1997; Lloyd et al., 1997; Zhu et al., 1998; Lin et al., 1998).”
BackgroundMethodResultInfluential
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975 · see citing works
Mice 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 · see citing works
p21 is a universal inhibitor of cyclin kinases
Xiong, Y., Hannon, G., Zhang, H., Casso, D., Kobayashi, R., & Beach, D. (1993) · Nature · doi:10.1038/366701a0 · Cited by 3,691 · see citing works
Inhibitors of mammalian G1 cyclin-dependent kinases.Preprint
Sherr, C. J., & Roberts, J. M. (1995) · Genes & Development · doi:10.1101/gad.9.10.1149 · Cited by 3,222 · see citing works
QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES
Todaro, G. J., & Green, H. (1963) · The Journal of Cell Biology · doi:10.1083/jcb.17.2.299 · Cited by 2,725 · see citing works
Production of high-titer helper-free retroviruses by transient transfection.
Pear, W. S., Nolan, G. P., Scott, M. L., & Baltimore, D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8392 · Cited by 2,267 · see citing works
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Deng, C., Zhang, P., Wade Harper, J., Elledge, S. J., & Leder, P. (1995) · Cell · doi:10.1016/0092-8674(95)90039-x · Cited by 2,113 · see citing works
Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., & Greider, C. W. (1997) · Cell · doi:10.1016/s0092-8674(01)80006-4 · Cited by 2,108 · see citing works
Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line
Morgenstern, J. P., & Land, H. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.12.3587 · Cited by 2,099 · see citing works
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · see citing works
ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626 · see citing works
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585 · see citing works
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 · see citing works
The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53
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
Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen
Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M., & Smith, J. R. (1994) · Experimental Cell Research · doi:10.1006/excr.1994.1063 · Cited by 1,351 · see citing works
The complexity of p53 modulation: emerging patterns from divergent signalsPreprint
Giaccia, A. J., & Kastan, M. B. (1998) · Genes & Development · doi:10.1101/gad.12.19.2973 · Cited by 1,303 · 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
Radiation-induced cell cycle arrest compromised by p21 deficiency
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J. (1995) · Nature · doi:10.1038/377552a0 · Cited by 1,242 · cited 3× · see citing works
“In response to g-radiation, p21 is strongly upregulated in a p53-dependent manner (see El-Deiry et al., 1993; Di Leonardo et al., 1994), and cells derived from p21-null mice arrest ine ciently upon g-radiation (Brugarolas et al., 1995; Deng et al., 1995).”
BackgroundMethodInfluential
DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts.
Di Leonardo, A., Linke, S. P., Clarkin, K., & Wahl, G. M. (1994) · Genes & Development · doi:10.1101/gad.8.21.2540 · Cited by 1,215 · see citing works
Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · cited 1× · see citing works
“In human cells, telomere attrition is directly implicated in triggering senescence (see for example Bodnar et al., 1998; Kiyono et al., 1998); but in rodent cells, senescence is independent of telomere shortening (Blasco et al., 1997; Carman et al., 1998; Russo et al., 1998).”
Background
The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2
Stott, F. J., Bates, S., James, M. C., McConnell, B. B., Starborg, M., Brookes, S., Palmero, I., Ryan, K. M., Hara, E., Vousden, K. H., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.5001 · Cited by 1,165 · see citing works
Correlation of Terminal Cell Cycle Arrest of Skeletal Muscle with Induction of p21 by MyoD
Halevy, O., Novitch, B. G., Spicer, D. B., Skapek, S. X., Rhee, J., Hannon, G. J., Beach, D., & Lassar, A. B. (1995) · Science · doi:10.1126/science.7863327 · Cited by 1,139 · see citing works
p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage.Preprint
Macleod, K. F., Sherry, N., Hannon, G. J., Beach, D., Tokino, T., Kinzler, K. W., Vogelstein, B., & Jacks, T. (1995) · Genes & Development · doi:10.1101/gad.9.8.935 · Cited by 1,119 · see citing works
Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
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 · see citing works
Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism.
Datto, M., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., & Wang, X. F. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5545 · Cited by 945 · see citing works
Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling
Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., & Lowe, S. W. (1998) · Genes & Development · doi:10.1101/gad.12.19.3008 · Cited by 945 · see citing works
p14ARF links the tumour suppressors RB and p53
Bates, S., Phillips, A. C., Clark, P. A., Stott, F., Peters, G., Ludwig, R. L., & Vousden, K. H. (1998) · Nature · doi:10.1038/25867 · Cited by 918 · see citing works
Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2
Kamijo, T., Weber, J. D., Zambetti, G., Zindy, F., Roussel, M. F., & Sherr, C. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8292 · Cited by 899 · see citing works
Induction of the growth inhibitor IGF-binding protein 3 by p53
Buckbinder, L., Talbott, R. L., Velasco-Miguel, S., Takenaka, I. M., Faha, B., Seizinger, B. R., & Kley, N. (1995) · Nature · doi:10.1038/377646a0 · Cited by 869 · see citing works
Senescence of human fibroblasts induced by oncogenic Raf
Zhu, J., Woods, D., McMahon, M., & Bishop, J. M. (1998) · Genes & Development · doi:10.1101/gad.12.19.2997 · Cited by 826 · see citing works
Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts
Brown, J. P., Wei, W., & Sedivy, J. M. (1997) · Science · doi:10.1126/science.277.5327.831 · Cited by 804 · see citing works
Tumor surveillance via the ARF–p53 pathwayPreprint
Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.19.2984 · Cited by 716 · see citing works
Raf-Induced Proliferation or Cell Cycle Arrest Is Determined by the Level of Raf Activity with Arrest Mediated by p21Cip1
Woods, D. B., Parry, D., Cherwinski, H. M., Bosch, E., Lees, E. M., & McMahon, M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.9.5598 · Cited by 639 · see citing works
Signaling to p53
Prives, C. (1998) · Cell · doi:10.1016/s0092-8674(00)81774-2 · Cited by 623 · see citing works
p19ARF links the tumour suppressor p53 to Ras
Palmero, I., Pantoja, C., & Serrano, M. (1998) · Nature · doi:10.1038/25870 · Cited by 617 · see citing works
E1A signaling to p53 involves the p19ARFtumor suppressorPreprint
de Stanchina, E., McCurrach, M. E., Zindy, F., Shieh, S.-Y., Ferbeyre, G., Samuelson, A. V., Prives, C. L., Roussel, M. F., Sherr, C. J., & Lowe, S. W. (1998) · Genes & Development · doi:10.1101/gad.12.15.2434 · Cited by 607 · see citing works
Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging
Zindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574 · see citing works
Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1
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 · see citing works
Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1
Olson, M. F., Paterson, H. F., & Marshall, C. J. (1998) · Nature · doi:10.1038/28425 · Cited by 469 · see citing works
High-Intensity Raf Signal Causes Cell Cycle Arrest Mediated by p21 Cip1
Sewing, A., Wiseman, B. S., Lloyd, A. C., & Land, H. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.9.5588 · Cited by 455 · see citing works
p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts.
Harvey, D. M., & Levine, A. J. (1991) · Genes & Development · doi:10.1101/gad.5.12b.2375 · Cited by 453 · see citing works
Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway
Pumiglia, K. M., & Decker, S. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.2.448 · Cited by 357 · see citing works
The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression.Preprint
Missero, C., Cunto, F. D., Kiyokawa, H., Koff, A., & Dotto, G. P. (1996) · Genes & Development · doi:10.1101/gad.10.23.3065 · Cited by 312 · see citing works
Increased 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 · see citing works
Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation
Brenner, A. J., Stampfer, M. R., & Aldaz, C. M. (1998) · Oncogene · doi:10.1038/sj.onc.1201919 · Cited by 272 · cited 1× · see citing works
“In addition to ®broblasts, the induction of p21 at senescence has been also observed in vascular endothelial cells (Watanabe et al., 1997), but not in T-lymphocytes or epithelial cells from several tissues (Rezniko et al., 1996; Foster et al., 1998; Brenner et al., 1998; Erickson et al., 1998).”
Background
Alterations in p53 and p16 INK4 Expression and Telomere Length during Spontaneous Immortalization of Li-Fraumeni Syndrome Fibroblasts
Rogan, E. M., Bryan, T. M., Hukku, B., Maclean, K. N., Chang, A. C.-M., Moy, E. L., Englezou, A., Warneford, S., Dalla‐Pozza, L., & Reddel, R. R. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.9.4745 · Cited by 250 · see citing works
Expression of cell cycle-dependent genes in young and senescent WI-38 fibroblasts.
Rittling, S. R., Brooks, K. M., Cristofalo, V. J., & Baserga, R. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.10.3316 · Cited by 241 · see citing works
Inactivation of p16 in Human Mammary Epithelial Cells by CpG Island Methylation
Foster, S. A., Wong, D. J., Barrett, M. T., & Galloway, D. A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.4.1793 · Cited by 229 · see citing works
Cooperating oncogenes converge to regulate cyclin/cdk complexes.Preprint
Lloyd, A. C., Obermüller, F., Staddon, S., Barth, C. F., McMahon, M., & Land, H. (1997) · Genes & Development · doi:10.1101/gad.11.5.663 · Cited by 224 · see citing works
Untitled work
(1996) · PubMed · Cited by 180 · see citing works
Loss of p 21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm -deficient mice
Wang, Y., Elson, A., & Leder, P. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.26.14590 · Cited by 170 · see citing works
Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies
Gire, V., & Wynford-Thomas, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1611 · Cited by 161 · see citing works
p21 Is a Critical CDK2 Regulator Essential for Proliferation Control in Rb-deficient Cells
Brugarolas, J., Bronson, R. T., & Jacks, T. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.2.503 · Cited by 153 · see citing works
Splicing into Senescence: The Curious Case of p16 and p19ARF
Haber, D. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80441-9 · Cited by 144 · see citing works
Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells
Watanabe, Y., Lee, S. W., Detmar, M. J., Ajioka, I., & Dvorak, H. F. (1997) · Oncogene · doi:10.1038/sj.onc.1201033 · Cited by 141 · see citing works
The Cat and Mouse Games That Genes, Viruses, and Cells Play
Weinberg, R. A. (1997) · Cell · doi:10.1016/s0092-8674(00)81897-8 · Cited by 137 · see citing works
Origins of G1 arrest in senescent human fibroblasts
Stein, G. H., & Dulić, V. (1995) · BioEssays · doi:10.1002/bies.950170610 · Cited by 135 · see citing works
Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence
Erickson, S., Sangfelt, O., Heyman, M. M., Castro, J., Einhorn, S., & Grandér, D. (1998) · Oncogene · doi:10.1038/sj.onc.1201965 · Cited by 125 · see citing works
Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status
Palmero, I., McConnell, B. B., Parry, D., Brookes, S., Hara, E., Bates, S., Jat, P., & Peters, G. G. (1997) · Oncogene · doi:10.1038/sj.onc.1201212 · Cited by 123 · see citing works
Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes
Metz, T. M., Harris, A. W., & Adams, J. M. (1995) · Cell · doi:10.1016/0092-8674(95)90049-7 · Cited by 122 · see citing works
Insulin-like growth factor binding protein 3 accumulates to high levels in culture medium of senescent and quiescent human fibroblasts.
Goldstein, S., Moerman, E. J., Jones, R. A., & Baxter, R. C. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.21.9680 · Cited by 104 · see citing works
Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atm−/− Mice
Xu, Y., Yang, E. M., Brugarolas, J., Jacks, T., & Baltimore, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.4385 · Cited by 103 · see citing works
Investigation of the role of G1/S cell cycle mediators in cellular senescence
Afshari, C. A., Vojta, P. J., Annab, L. A., Futreal, P. A., Willard, T. B., & Barrett, J. C. (1993) · Experimental Cell Research · doi:10.1006/excr.1993.1306 · Cited by 100 · see citing works
The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2
Jones, S. N., Sands, A., Hancock, A. R., Vogel, H. S., Donehower, L. A., Linke, S. P., Wahl, G. M., & Bradley, A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.14106 · Cited by 87 · see citing works
Genetic analysis of cellular senescence
Vojta, P. J., & Barrett, J. C. (1995) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00002-w · Cited by 80 · see citing works
Expression of p21 is not required for senescence of human fibroblasts.
Medcalf, A. S. C., Klein-Szanto, A. J., & Cristofalo, V. J. (1996) · PubMed · Cited by 54 · see citing works
A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization
Russo, I., Silver, A. R., Cuthbert, A. P., Griffin, D. K., Trott, D. A., & Newbold, R. F. (1998) · Oncogene · doi:10.1038/sj.onc.1202261 · Cited by 47 · see citing works
Cellular Senescence in Telomerase-Expressing Syrian Hamster Embryo Cells
Carman, T. A., Afshari, C. A., & Barrett, J. C. (1998) · Experimental Cell Research · doi:10.1006/excr.1998.4207 · Cited by 38 · see citing works
Molecular Aspects of the Relationship between Cancer and Aging: Tumor Suppressor Activity During Cellular Senescence
Garkavtsev, I., Hull, C. M., & Riabowol, K. T. (1998) · Experimental Gerontology · doi:10.1016/s0531-5565(97)00086-7 · Cited by 29 · see citing works
Adenovirus type 12 early region 1B 54K protein significantly extends the life span of normal mammalian cells in culture
Gallimore, P. H., Lecane, P. S., Roberts, S., Rookes, S. M., Grand, R. J. A., & Parkhill, J. (1997) · Journal of Virology · doi:10.1128/jvi.71.9.6629-6640.1997 · Cited by 23 · see citing works
Loss of p21CIP1/WAF1 does not recapitulate accelerated malignant conversion caused by p53 loss in experimental skin carcinogenesis
Weinberg, W. C., Montano, N. E., & Deng, C. (1997) · Oncogene · doi:10.1038/sj.onc.1201230 · Cited by 20 · see citing works
Clonal Nature of Spontaneously Immortalized 3T3 Cells
Rittling, S. R. (1996) · Experimental Cell Research · doi:10.1006/excr.1996.0337 · Cited by 18 · see citing works
Expression of p24, a novel p21 Waf1/Cip1/Sdi1 -related protein, correlates with measurement of the finite proliferative potential of rodent embryo fibroblasts
Mazars, G. R., & Jat, P. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.1.151 · Cited by 18 · see citing works
Age-dependent alterations of c-fos and growth regulation in human fibroblasts expressing the HPV16 E6 protein.
Yan, Y., Ouellette, M. M., Shay, J. W., & Wright, W. E. (1996) · Molecular Biology of the Cell · doi:10.1091/mbc.7.6.975 · Cited by 9 · see citing works

Flagged first, then by citations

1 of the 78 references couldn’t be matched to a known paper.

Sorted by citations

The 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
“However, cells lacking Cip1 are not immortal and undergo efficient p19Arf-induced arrest (Pantoja and Serrano, 1999; Modestou et al. 2001).”
Background
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
The signals and pathways activating cellular senescence
Ben-Porath, I., & Weinberg, R. A. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.10.013 · Cited by 1,046 · see citing works
The INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 984 · see citing works
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
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 · see citing works
Akt Determines Replicative Senescence and Oxidative or Oncogenic Premature Senescence and Sensitizes Cells to Oxidative Apoptosis
Nogueira, V., Park, Y., Chen, C.-C., Xu, P.-Z., Chen, M.-L., Tonic, I., Unterman, T., & Hay, N. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.11.003 · Cited by 780 · see citing works
“Population Doubling Serial 3T3 cultivation was carried out as described previously (Pantoja and Serrano, 1999).”
Method
Cellular Senescence
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · see citing works
Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence
Kortlever, R. M., Higgins, P. J., & Bernards, R. (2006) · Nature Cell Biology · doi:10.1038/ncb1448 · Cited by 637 · see citing works
Targeted disruption of the three Rb-related genes leads to loss of G 1 control and immortalization
Sage, J., Mulligan, G. J., Attardi, L. D., Miller, A., Chen, S., Williams, B., Theodorou, E., & Jacks, T. (2000) · Genes & Development · doi:10.1101/gad.843200 · Cited by 582 · see citing works
“The p21 cell cycle inhibitor has also been shown to play a role similar to that of p16 in senescence in human cells, although its role in mouse cells is less clear (Brown et al. 1997; Pantoja and Serrano 1999).”
Background
Comparative biology of mouse versus human cells: modelling human cancer in mice
Rangarajan, A., & Weinberg, R. A. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1235 · Cited by 567 · see citing works
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 · see citing works
'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
García‐Cao, I., García‐Cao, M., Martín‐Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J., Blasco, M. A., & Serrano, M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf595 · Cited by 529 · see citing works
Delayed ageing through damage protection by the Arf/p53 pathway
Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., Flores, J. M., Viña, J., Blasco, M. A., & Serrano, M. (2007) · Nature · doi:10.1038/nature05949 · Cited by 466 · see citing works
Self-citation
LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint
Dimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445 · see citing works
“These data are consistent with the absence of these phenotypes in p21-deficient cells (Pantoja and Serrano, 1999).”
Oncogenic functions of tumour suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumour-promoting activities of stromal fibroblasts
Roninson, I. B. (2002) · Cancer Letters · doi:10.1016/s0304-3835(01)00847-3 · Cited by 443 · see citing works
Ablation of the Retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
“This phenomenon, known as contact inhibition, was shown to be accompanied by increased p27KIP1 and decreased cyclin D1 levels (Polyak et al. 1994; St. Croix et al. 1998).”
Background
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 · see citing works
Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis
González-Suárez, E., Samper, E., Flores, J. M., & Blasco, M. A. (2000) · Nature Genetics · doi:10.1038/79089 · Cited by 347 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
“However, MEFs from p21 null mice senesce normally (Pantoja and Serrano 1999).”
Background
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 · see citing works
What has senescence got to do with cancer?
Dimri, G. P. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.025 · Cited by 313 · see citing works
“It has also been suggested that p21 may not be the sole conduit of p53 during senescence induction in mouse cells (Pantoja and Serrano, 1999).”
Background
Senescence, apoptosis and therapy — cutting the lifelines of cancer
Schmitt, C. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1044 · Cited by 295 · see citing works
A critical role for telomeres in suppressing and facilitating carcinogenesis
Artandi, S. E., & DePinho, R. A. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00047-7 · Cited by 318 · 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
Global loss of imprinting leads to widespread tumorigenesis in adult mice
Holm, T. M., Jackson‐Grusby, L., Brambrink, T., Yamada, Y., Rideout, W. M., & Jaenisch, R. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.09.007 · Cited by 252 · see citing works
“The p21CIP1 cell cycle inhibitor has been shown to have a similar function as p16INK4A in senescing human cells, although its role in mouse cells is less clear (Brown et al., 1997; Pantoja and Serrano, 1999).”
Background
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 · see citing works
“Second, ectopic expression of Arf arrested p21 / MEFs (25), while it could not arrest p21 / human fibroblasts (this communication).”
BackgroundInfluential
Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208 · see citing works
Deconstructing p53 transcriptional networks in tumor suppression
Bieging, K. T., & Attardi, L. D. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.10.006 · Cited by 194 · see citing works
Frequency of p16 INK4A alterations and k- ras mutations in intrahepatic cholangiocarcinoma of the liver
Tannapfel, A., Benicke, M., Katalinic, A., Uhlmann, D., Köckerling, F., Hauss, J., & Wittekind, C. (2000) · Gut · doi:10.1136/gut.47.5.721 · Cited by 193 · see citing works
Ras proteins in the control of the cell cycle and cell differentiation
Crespo, P., & León, J. (2000) · Cellular and Molecular Life Sciences · doi:10.1007/pl00000645 · Cited by 189 · see citing works
Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner
Shao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D. (2014) · Blood · doi:10.1182/blood-2013-07-515619 · Cited by 165 · see citing works
Genome Stability Requires p53
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
Tbx2 Directly Represses the Expression of the p21WAF1 Cyclin-Dependent Kinase Inhibitor
Prince, S., Carreira, S., Vance, K. W., Abrahams, A., & Goding, C. R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3286 · Cited by 160 · see citing works
Uncoupling between Phenotypic Senescence and Cell Cycle Arrest in Aging p21-Deficient Fibroblasts
Dulić, V., Beney, G.-E., Frebourg, G., Drullinger, L. F., & Stein, G. H. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6741-6754.2000 · Cited by 149 · see citing works
“Nevertheless, as described previously (45), late-passage p21 MEFs have a senescent morphology (but not SA–b-Gal) when their population expansion ceases (or reaches a plateau in the case of cultures that eventually immortalize) owing to crisislike events.”
BackgroundResult
TBX-3, the Gene Mutated in Ulnar-Mammary Syndrome, Is a Negative Regulator of p19 and Inhibits Senescence
Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110492200 · Cited by 154 · see citing works
Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence
Larsson, L. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.10.005 · Cited by 147 · see citing works
Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin
Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L. T., & Serrano, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0200 · Cited by 140 · see citing works
“genotype were obtained as previously described (35) and grown in the”
Method
Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescencePreprint
Zou, X., Ray, D., Aziyu, A., Christov, K. T., Boiko, A. D., Gudkov, A. V., & Kiyokawa, H. (2002) · Genes & Development · doi:10.1101/gad.1033002 · Cited by 143 · see citing works
“However, p21Cip1/Waf1-null MEFs with intact Cdk4 senesce normally (Pantoja and Serrano 1999), andMEFs from p21Cip1/Waf1, Cdk4-double null mice poorly undergo transformation upon expression of H-RasVal12 and DNp53 (X. Zou and H. Kiyokawa, unpubl.).”
Background
A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19 ARF –p53 signalingPreprint
Shvarts, A., Brummelkamp, T. R., Scheeren, F., Koh, E., Daley, G. Q., Spits, H., & Bernards, R. (2002) · Genes & Development · doi:10.1101/gad.929302 · Cited by 142 · see citing works
“…genetic ablation of p16INK4A alone or p21cip1 in mouse embryonic fibroblasts (MEFs) does not render cells resistant to the induction of senescence (Pantoja and Serrano 1999; Krimpenfort et al. 2001), even though enforced expression of p16INK4A or p21cip1 (McConnell et al. 1998; Dai and Enders…”
Background
The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation
Zupkovitz, G., Grausenburger, R., Brunmeir, R., Senese, S., Tischler, J., Jurkin, J., Rembold, M., Meunier, D., Egger, G., Lagger, S., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01500-09 · Cited by 138 · see citing works
“However, data obtained in studies with human and mouse fibroblasts showed in part divergent results with respect to the role of p21 during immortalization (7, 37).”
Result
Increased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 137 · see citing works
Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo
Takeuchi, S., Takahashi, A., Motoi, N., Yoshimoto, S., Tajima, T., Yamakoshi, K., Hirao, A., Yanagi, S., Fukami, K., Ishikawa, Y., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0801 · Cited by 136 · see citing works
The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescencePreprint
Aksoy, O., Chicas, A., Zeng, T., Zhao, Z., McCurrach, M. E., Wang, X., & Lowe, S. W. (2012) · Genes & Development · doi:10.1101/gad.196238.112 · Cited by 127 · see citing works
“…et al. 2010). p53 is a sequence-specific DNAbinding transcription factor that promotes senescence in part through its ability to induce the cyclin-dependent kinase (CDK) inhibitor p21CDKN1A and the anti-proliferative microRNA miR-34 (Pantoja and Serrano 1999; He et al. 2007; Chicas et al. 2010).”
Background
Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging
Zhang, H. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20919 · Cited by 128 · see citing works
“Interestingly, mouse embryo fibroblasts (MEFs) carrying a null mutation in p21 undergo senescence normally (Pantoja and Serrano, 1999), indicating that p21 is not a critical link downstream of p53 during senescence in rodent cells.”
Background
Does p53 affect organismal aging?
Donehower, L. A. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10104 · Cited by 155 · see citing works
“In other instances, a p53-dependent induction of senescence could be generated in the absence of p21 (Pantoja and Serrano, 1999; Groth et al., 2000; Wei et al., 2001).”
Background
Cyclin-dependent kinase inhibitor p21Waf1: Contemporary view on its role in senescence and oncogenesis
Romanov, V. S., Поспелов, В. А., & Pospelova, T. V. (2012) · Biochemistry (Moscow) · doi:10.1134/s000629791206003x · Cited by 122 · see citing works
E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest
Rowland, B. D., Denissov, S. G., Douma, S., Stunnenberg, H. G., Bernards, R., & Peeper, D. S. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00085-5 · Cited by 120 · see citing works
“…still undergo RASV12- or p19ARF-induced arrest, p21CIP1 likely is not a critical p19ARF/p53 target gene in(Bruce et al., 2000; Koh et al., 1995; Lukas et al., 1995; Medema et al., 1995). p19ARF, too, is a tumor suppressor gene that has this setting (Groth et al., 2000; Pantoja and Serrano, 1999).”
Background
Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence.
Krones-Herzig, A., Adamson, E., & Mercola, D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2628034100 · Cited by 118 · see citing works
p53 downstream target genes and tumor suppression: a classical view in evolution
Rozan, L. M., & El‐Deiry, W. S. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402058 · Cited by 115 · see citing works
A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence
Peeper, D. S., Shvarts, A., Brummelkamp, T. R., Douma, S., Koh, E. Y., Daley, G. Q., & Bernards, R. (2002) · Nature Cell Biology · doi:10.1038/ncb742 · Cited by 110 · see citing works
A Senescence-Like Cell-Cycle Arrest Occurs During Megakaryocytic Maturation: Implications for Physiological and Pathological Megakaryocytic Proliferation
Besancenot, R., Chaligné, R., Tonetti, C., Pasquier, F., Marty, C., Lécluse, Y., Vainchenker, W., Constantinescu, S. N., & Giraudier, S. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000476 · Cited by 107 · see citing works
Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesisPreprint
Inoue, K., Wen, R., Rehg, J. E., Adachi, M., Cleveland, J. L., Roussel, M. F., & Sherr, C. J. (2000) · Genes & Development · doi:10.1101/gad.14.14.1797 · Cited by 107 · see citing works
“Lymphomas were classified according to the criteria of Pattengale and Firth (1986).”
Method
Loss of p53 Induces Tumorigenesis in p21-Deficient Mesenchymal Stem Cells
Rodrı́guez, R., Rubio, R., Masip, M., Catalina, P., Nieto, A., de la Cueva, T., Arriero, M., Martín, N. S., de la Cueva, E., Balomenos, D., et al. (2009) · Neoplasia · doi:10.1593/neo.81620 · Cited by 105 · see citing works
“Moreover, spontaneous immortalization of murine fibroblasts is frequently associated with a mutation of p53 [41], and wild-type and p21 MEF cultures acquire alterations in p53 [42].”
Background
p53-Dependent and -Independent Functions of the Arf Tumor SuppressorPreprint
Sherr, C. J., Bertwistle, D., den Besten, W., KUO, M.-L., SUGIMOTO, M., Tago, K., Williams, R. T., Zindy, F., & Roussel, M. F. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.004 · Cited by 103 · see citing works
“Although these manipulations ultimately prove toxic, inhibition of Arf-induced sumoylation of Mdm2 had no immediate effect on p53 stabilization or on the induction of canonical p53-responsive genes, such as Cip1 or Mdm2 itself (Tago et al. 2005).”
BackgroundInfluential
Multiple E2F-Induced MicroRNAs Prevent Replicative Stress in Response to Mitogenic Signaling
Bueno, M. J., de Cedrón, M. G., Laresgoiti, U., Fernández‐Piqueras, J., Zubiaga, A. M., & Malumbres, M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01372-09 · Cited by 100 · see citing works
“However, downregulation or p21 does not promote cell cycle progression in primary MEFs (56), and indeed, it may be important to support cyclin D-CDK4 activity in these primary cells (64).”
Background
Arf induces p53-dependent and -independent antiproliferative genes.
Kuo, M.-L., Duncavage, E. J., Mathew, R., den Besten, W., Pei, D., Naeve, D., Yamamoto, T. S., Cheng, C., Sherr, C. J., & Roussel, M. F. (2003) · PubMed · Cited by 99 · see citing works
Transcriptional regulation of cellular senescence
Lanigan, F., Geraghty, J. G., & Bracken, A. P. (2011) · Oncogene · doi:10.1038/onc.2011.34 · Cited by 95 · see citing works
“Interestingly, in mouse fibroblasts, the loss of p21 does not recapitulate p53 loss, and these cells still undergo cellular senescence (Pantoja and Serrano, 1999).”
Integration of positive and negative growth signals during ras pathway activation in vivo
Frame, S., & Balmain, A. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00052-0 · Cited by 98 · see citing works
Oncogenic Ras Induces p19ARF and Growth Arrest in Mouse Embryo Fibroblasts Lacking p21Cip1 and p27Kip1 without Activating Cyclin D-dependent Kinases
Groth, A., Weber, J. D., Willumsen, B. M., Sherr, C. J., & Roussel, M. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003417200 · Cited by 92 · see citing works
Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control
Takahashi, A., Ohtani, N., & Hara, E. (2007) · Cell Division · doi:10.1186/1747-1028-2-10 · Cited by 96 · see citing works
“However, since mutations in the p21Waf1/Cip1/Sdi1 gene are rarely observed in human cancers and mice lacking p21Waf1/Cip1/ Sdi1 gene do not exhibit any predisposition to spontaneous tumor formation [37-40], it remains unclear whether p21Cip1/Waf1/Sdi1 indeed plays a key role in tumor suppression in vivo.”
Background
Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model
Adnane, J., Jackson, R. J., Nicosia, S. V., Cantor, A. B., Pledger, W. J., & Sebti, S. M. (2000) · Oncogene · doi:10.1038/sj.onc.1203956 · Cited by 91 · see citing works
“This is in agreement with a study that showed that p21-null primary murine ®broblasts were resistant to transfor- Oncogene mation by oncogenic ras and that additional changes were necessary to achieve a fully transformed phenotype (Pantoja and Serrano, 1999).”
Result
Lentivector-Mediated Transfer of Bmi-1 and Telomerase in Muscle Satellite Cells Yields a Duchenne Myoblast Cell Line with Long-Term Genotypic and Phenotypic Stability
Cudré-Mauroux, C., Occhiodoro, T., König, S., Salmon, P., Bernheim, L., & Trono, D. (2003) · Human Gene Therapy · doi:10.1089/104303403322495034 · Cited by 86 · see citing works
“In the contrary, MEFs from p21 null mice senesce normally (Pantoja and Serrano, 1999).”
Replicative senescence revisited.
Marcotte, R., & Wang, E. (2002) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/57.7.b257 · Cited by 86 · see citing works
“Pantoja C, Serrano M. Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.”
BackgroundInfluential
Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer
Castillo, S. D., Matheu, A., Mariani, N., Carretero, J., López‐Ríos, F., Lovell-Badge, R. H., & Sánchez‐Céspedes, M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-3506 · Cited by 86 · see citing works
“Mouse embryo fibroblasts (MEF) were isolated and cultured as previously described (26) from Sox4þ/þ, Sox4þ/ , and Sox4 / E13.”
Method
Tumor suppression by p53: making cells senescent.
Qian, Y., & Chen, X. (2010) · PubMed · doi:10.14670/hh-25.515 · Cited by 85 · see citing works
“In agreement with this, MEFs derived from p21null mice eventually enter senescence (Pantoja and Serrano, 1999).”
Exploiting tumor cell senescence in anticancer therapy
Lee, M., & Lee, J. (2014) · BMB Reports · doi:10.5483/bmbrep.2014.47.2.005 · Cited by 83 · see citing works
“stream effector of p53 during senescence in mouse cells (39, 40).”
Background
Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation
Fiorentino, F. P., Tokgün, P. E., Solé‐Sánchez, S., Giampaolo, S., Tokgün, O., Jauset, T., Kohno, T., Perucho, M., Soucek, L., & Yokota, J. (2016) · Oncotarget · doi:10.18632/oncotarget.8826 · Cited by 80 · see citing works
“Cell growth assays were performed with a modification of serial cultivation method [49].”
The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence
Haferkamp, S., Tran, S. L., Becker, T. M., Scurr, L. L., Kefford, R. F., & Rizos, H. (2009) · Aging · doi:10.18632/aging.100051 · Cited by 77 · see citing works
Frequent k- ras -2 mutations and p16INK4Amethylation in hepatocellular carcinomas in workers exposed to vinyl chloride
Weihrauch, M., Benicke, M., Lehnert, G., Wittekind, C., Wrbitzky, R., & Tannapfel, A. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2000.1675 · Cited by 77 · see citing works
Therapeutic targeting of replicative immortality
Yaswen, P., MacKenzie, K. L., Keith, W. N., Hentosh, P., Rodier, F., Zhu, J., Firestone, G. L., Matheu, A., Carnero, A., Bilsland, A. E., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.03.007 · Cited by 74 · see citing works
“However, in MEFs, the absence of 21 does not prevent senescence [106,107].”
Background
YPEL3, a p53-Regulated Gene that Induces Cellular Senescence
Kelley, K. D., Miller, K. R., Todd, A., Kelley, A. R., Tuttle, R., & Berberich, S. J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3219 · Cited by 73 · see citing works
“Although it is accepted that cyclindependent kinase inhibitor and p53 target gene p21 is induced as cells undergo senescence, in some cell systems, the loss of p21 leads to senescence bypass (7); yet in other cell systems, p21-null cells can still undergo a ras-mediated senescence (8).”
Background
LMP1 of Epstein–Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression
Yang, X., He, Z., Xin, B., & Cao, L. (2000) · Oncogene · doi:10.1038/sj.onc.1203515 · Cited by 71 · see citing works
“Mutation in p16 or p53, but not p21, abolishes oncogene ras induced premature senescence of MEF cells (Serrano et al., 1997; Pantoja and Serrano, 1999).”
Background
Markers of cellular senescence.
Carnero, A. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_4 · Cited by 68 · see citing works
Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling
Geserick, C., Tejera, Á. M., González‐Suárez, E., Klatt, P., & Blasco, M. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209465 · Cited by 70 · see citing works
“Serial 3T3 cultivation and calculation of population doublings, as well as colony-formation assays were performed as described (Pantoja and Serrano, 1999).”
Method
Loss of CCAAT/enhancer binding protein δ promotes chromosomal instability
Huang, A., Montagna, C., Sharan, S., Ni, Y., Ried, T., & Sterneck, E. (2004) · Oncogene · doi:10.1038/sj.onc.1207285 · Cited by 70 · see citing works
“However, the MEF display G1 checkpoint defects, and the mutation indeed contributes in vivo to tumorigenesis when induced by, for example, oncogenic Ras or chemical carcinogenesis (Deng et al., 1995; Pantoja and Serrano, 1999; Jackson et al., 2002).”
Background
Heterozygous deletion of the Williams–Beuren syndrome critical interval in mice recapitulates most features of the human disorder
Puimedon, M. S., Sahún, I., Velot, É., Dubus, P. R., Borralleras, C., Rodrigues, A. J., Valero, M. C., Valverde, O., Sousa, N., Hérault, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu368 · Cited by 69 · see citing works
Identification of a Candidate Tumor-Suppressor Gene Specifically Activated during Ras-Induced Senescence
Barradas, M., Gonos, E. S., Zebedee, Z., Kolettas, E., Petropoulou, C., Delgado, M. D., León, J., Hara, E., & Serrano, M. (2002) · Experimental Cell Research · doi:10.1006/excr.2001.5434 · Cited by 66 · see citing works
The Cyclin-dependent Kinase Inhibitors p27Kip1 and p21Cip1 Cooperate to Restrict Proliferative Life Span in Differentiating Ovarian Cells
Jirawatnotai, S., Moons, D. S., Stocco, C. O., Franks, R. R., Hales, D. B., Gibori, G., & Kiyokawa, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301206200 · Cited by 64 · see citing works
H-Ras-driven tumoral maintenance is sustained through caveolin-1-dependent alterations in calcium signaling
Rimessi, A., Marchi, S., Patergnani, S., & Pinton, P. (2013) · Oncogene · doi:10.1038/onc.2013.192 · Cited by 63 · see citing works
ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells
Wang, Y., Godin-Heymann, N., WANG, X.-D., Bergamaschi, D., Llanos, S., & Lü, X. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.3 · Cited by 60 · see citing works
p53-dependent senescence delays Eμ-myc-induced B-cell lymphomagenesis
Post, S. M., Quintás‐Cardama, A., Terzian, T., Smith, C., Eischen, C. M., & Lozano, G. (2009) · Oncogene · doi:10.1038/onc.2009.423 · Cited by 58 · see citing works
“Transfection of oncogenic Ras induces senescence in MEFs carrying wild-type p53, which results in low transformation potential (Serrano et al., 1997; Pantoja and Serrano, 1999).”
Background
Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression
Efeyan, A., Murga, M., Martínez-Pastor, B., Ortega-Molina, A., Soria, R., Collado, M., Fernández-Capetillo, Ó., & Serrano, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005475 · Cited by 58 · see citing works
“5 embryos as previously described [52] and grown in Dulbecco’s Minimum Essential Media (DMEM, Invitrogen, Grand Island, NY, USA) supplemented with 10% FBS (Hyclone, Logan, UT).”
Method
Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors
Baek, K., Bhang, D., Zaslavsky, A., Wang, L.-C., Vachani, A., Kim, C. F., Albelda, S. Μ., Evan, G. I., & Ryeom, S. W. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67465 · Cited by 56 · see citing works
“Consistent with studies showing that p21 cip1 induction, while necessary, is not sufficient for oncogene-induced senescence (28, 35, 36), p21 cip1 was induced after oncogenic Ras activation — but at a substantially lower level in the absence of TSP-1 — in lung fibroblasts, lung epithelial cells,…”
Cell-specific pattern of berberine pleiotropic effects on different human cell lines
Agnarelli, A., Natali, M., Garcia‐Gil, M., Pesi, R., Tozzi, M. G., Ippolito, C., Bernardini, N., Vignali, R., Batistoni, R., Bianucci, A. M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-28952-3 · Cited by 57 · see citing works
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence
Kalinin, A., Zubkova, E., & Menshikov, M. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417423 · Cited by 58 · see citing works
“For example, cellular senescence is possible in primary ﬁbroblasts from p21 knockout mice, and resistance to senescence is observed in certain mouse hepatic tumor cells despite p21CIP1/WAF1 expression [30].”
Background
Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge
Gomez-Sanchez, J. A., Gomis-Coloma, C., Morenilla‐Palao, C., Peiró, G., Serra, E., Serrano, M., & Cabedo, H. (2013) · Brain · doi:10.1093/brain/awt130 · Cited by 56 · see citing works
“However, it has been shown that p21cip / fibroblasts can enter the senescence programme (Pantoja and Serrano, 1999).”
Background
H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism
Delgado, M. D., Vaque, J. P., Arozarena, I., Lopez-Ilasaca, M. A., Martínez, C., Crespo, P., & León, J. (2000) · Oncogene · doi:10.1038/sj.onc.1203384 · Cited by 55 · see citing works
“…mechanisms could operate subsequently to p21WAF1 mediated growth arrest, as autophagic degeneration (Chi et al., 1999) or cellular senescence (Serrano et al., 1997; Fang et al., 1999) although in murine ®broblasts p21WAF1 is not essential for Ras-mediated senescence (Pantoja and Serrano, 1999).”
Background
Cellular senescence or stemness: hypoxia flips the coin
Otero-Albiol, D., & Carnero, A. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02035-0 · Cited by 53 · see citing works
The ink4a/arf Tumor Suppressors Cooperate with p21 in the Processes of Mouse Epidermal Differentiation, Senescence, and Carcinogenesis
Paramio, J. M., Segrelles, C., Ruiz, S., Martín‐Caballero, J., Page, A., Martínez, J. L., Serrano, M., & Jorcano, J. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105650200 · Cited by 51 · see citing works
Bcl-2 protects against oxidative stress while inducing premature senescence
López‐Díazguerrero, N. E., López-Araiza, H., Conde-Pérezprina, J. C., Bucio, L., Cárdenas‐Aguayo, M. D. C., Ventura, J. L., Covarrubias, L., Gutiérrez‐Ruíz, M. C., Zentella‐Dehesa, A., & Königsberg, M. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.11.002 · Cited by 50 · see citing works
Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
Lin, S., Yang, J., ELKAHLOUN, A. G., Bandyopadhyay, A. M., Wang, L., Cornell, J. E., Yeh, I., Agyin, J. K., Tomlinson, G. E., & Sun, L. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0849 · Cited by 49 · see citing works
“Published studies have shown that deletion of p21 gene is not sufficient for mouse fibroblasts to bypass Ras-induced senescence (Pantoja and Serrano, 1999) but is sufficient for the transformation of mouse keratinocytes by Ras (Missero et al.”
Background
Melanomagenesis: Overcoming the barrier of melanocyte senescence
Ha, L., Merlino, G. T., & Sviderskaya, E. V. (2008) · Cell Cycle · doi:10.4161/cc.7.13.6230 · Cited by 46 · see citing works
Animal and human models to understand ageing
Lees, H., Walters, H., & Cox, L. S. (2016) · Maturitas · doi:10.1016/j.maturitas.2016.06.008 · Cited by 47 · see citing works
“Induction of senescence in mice relies heavily on the p16 cyclin kinase inhibitor CDKN2A, while p21 CDKN1A may be more important in some cell types in humans [73].”
Background
The Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis
Dannenberg, J.-H., & te Riele, H. P. J. (2006) · Results and Problems in Cell Differentiation · doi:10.1007/400_002 · Cited by 47 · see citing works
Senescence-like changes induced by expression of p21Waf1/Cip1 in NIH3T3 cell line
Chen, X., Zhang, W., Gao, Y., Su, X., & Zhai, Z. H. (2002) · Cell Research · doi:10.1038/sj.cr.7290129 · Cited by 47 · see citing works
“Although the importance of p21 on senescence has been well reported[6-9], the question of whether p21 is essential for the establishment of senescence still needs to be answered definitely, at least in murine cells[10-12].”
Background
Oncogene-induced senescence: An essential role for Runx
Terry, A., Cameron, E. R., Neil, J. C., & Kilbey, A. (2008) · Cell Cycle · doi:10.4161/cc.6368 · Cited by 46 · see citing works
Cellular Senescence as a Target in Cancer Control
Vergel, M., Marín, J., Estévez, P., & Carnero, A. (2010) · Journal of Aging Research · doi:10.4061/2011/725365 · Cited by 43 · see citing works
“Eukaryotic cells cannot replicate the very ends of their chromosomes, the telomeres, resulting in shortening their lengths with every cell division until they reach a critical threshold, at which point cells stop replicating [11].”
Background
p21 as a Transcriptional Co-Repressor of S-Phase and Mitotic Control Genes
Ferrándiz, N., Caraballo, J. M., García-Gutiérrez, L., Devgan, V., Rodríguez‐Paredes, M., Lafita‐Navarro, M. C., Bretones, G., Quintanilla, A., Muñoz-Alonso, M. J., Blanco, R. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037759 · Cited by 44 · see citing works
“inducer of senescence [15,16,17] or differentiation (reviewed in [18]).”
Background
Secretome of Human Fetal Mesenchymal Stem Cell Ameliorates Replicative Senescence
Wang, B., Lee, W., Huang, B., Zhang, J., Wu, T., Jiang, X., Wang, C. C., & Li, G. (2016) · Stem Cells and Development · doi:10.1089/scd.2016.0079 · Cited by 44 · see citing works

Cellular senescence induced by p53‐ras cooperation is independent of p21waf1 in murine embryo fibroblasts
Castro, M. E., Guijarro, M. V., Moneo, V., & Carnero, A. (2004) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20079 · Cited by 20 · see citing works
Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence
Benanti, J. A., & Galloway, D. A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.7.2842-2852.2004 · Cited by 103 · see citing works
Escape from premature senescence is not sufficient for oncogenic transformation by Ras
Peeper, D. S., Dannenberg, J., Douma, S., Riele, H. T., & Bernards, R. (2001) · Nature Cell Biology · doi:10.1038/35055110 · Cited by 103 · see citing works
Activation of p53/p21waf1 pathway is associated with senescence during v-Ha-ras transformation of immortal C2C12 myoblasts.
D’Orazi, G., Soddu, S., & Sacchi, A. (2001) · PubMed · Cited by 3 · see citing works
The Normal Response to RAS: Senescence or Transformation?
Benanti, J. A., & Galloway, D. (2004) · Cell Cycle · doi:10.4161/cc.3.6.948 · Cited by 39 · see citing works

Authors: Pantoja, C., & Serrano, M.
Affiliations: Consejo Superior de Investigaciones Científicas (ES)
ORCID: Pantoja, Cristina
Serrano, Manuel
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 1999-09-02
Volume: 18
Issue: 35
Pages: 4974-4982
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1202880
OpenAlex: W2081779271
Cited by: 201
References: 78
Citations by year: 2025: 3 · 2023: 6 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 6
FWCI: 8.20
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
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: p21, cellular senescence, oncogenic Ras, oncogenic transformation, p53, p16INK4a, cell cycle inhibitors, fibroblasts, cell immortalization
MeSH terms: Animals, Cell Cycle, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, Cells, Cultured, Doxorubicin, Fibroblasts, Serial Passage, Transduction, Genetic, Oncogene Protein p21(ras), Gene Expression, Tumor Suppressor Protein p53, Cyclins, 3T3 Cells, Cellular Senescence, Gene Deletion, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Mice

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

Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks