Radiation-induced cell cycle arrest compromised by p21 deficiency
Abstract
The protein p21 is a dual inhibitor of cyclin-dependent kinases and proliferating-cell nuclear antigen (PCNA), both of which are required for passage through the cell cycle. The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21 has also been implicated in cell senescence and in cell-cycle withdrawal upon terminal differentiation. Here we investigate the role of p21 in these processes using chimaeric mice composed partly of p21-/- and partly of p21+/+ cells. Immunohistochemical studies of the p21+/+ and p21-/- components of adult small intestine indicated that deletion of p21 has no detectable effect on the migration-associated differentiation of the four principal intestinal epithelial cell lineages or on p53-dependent apoptosis following irradiation. However, p21-/- mouse embryo fibroblasts are impaired in their ability to undergo G1 arrest following DNA damage.
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p21 is required for p53-mediated G1/S cell cycle arrest.
“p21 is required for p53-mediated G1/S146, 147, 148 and also for G2/M cell cycle arrest.149”
From Census and evaluation of p53 target genes (2017) · cites this paper as [147]
Developmental senescence is not required for embryogenesis because embryos lacking p21 show minimal or no developmental defects.
“Surprisingly, developmental senescence is not required for embryogenesis because embryos lacking p21 show minimal or no developmental defects [56].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [56]
Cites
Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
Gavrieli, Y., Sherman, Y., & Ben-Sasson, S. A. (1992) · The Journal of cell biology · doi:10.1083/jcb.119.3.493 · Cited by 9,444 · see citing works
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
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
Self-citationKastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047 · see citing works
Self-citationAltering the Genome by Homologous Recombination
Capecchi, M. R. (1989) · Science · doi:10.1126/science.2660260 · Cited by 2,037 · see citing works
Effects of an Rb mutation in the mouse
Jacks, T., Fazeli, A., Schmitt, E. M., Bronson, R. T., Goodell, M. A., & Weinberg, R. A. (1992) · Nature · doi:10.1038/359295a0 · Cited by 1,755 · see citing works
Self-citationMansour, S. L., Thomas, K. R., & Capecchi, M. R. (1988) · Nature · doi:10.1038/336348a0 · Cited by 1,683 · see citing works
The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA
Waga, S., Hannon, G. J., Beach, D., & Stillman, B. (1994) · Nature · doi:10.1038/369574a0 · Cited by 1,655 · see citing works
Self-citationDulić, V., Kaufmann, W. K., Wilson, S. J., Tisty, T. D., Lees, E., Harper, J. W., Elledge, S. J., & Reed, S. I. (1994) · Cell · doi:10.1016/0092-8674(94)90379-4 · Cited by 1,465 · 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
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
Self-citationp53-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
Self-citationTeratocarcinomas and Embryonic Stem Cells: A Practical Approach
Robertson, E. J., & Beddington, R. (1988) · Development · doi:10.1242/dev.102.1.3 · Cited by 1,034 · see citing works
p53-Independent Expression of p21 Cip1 in Muscle and Other Terminally Differentiating Cells
Parker, S. B., Gregor Eichele, C., Zhang, P., Rawls, A., Sands, A., Bradley, A., Olson, E. N., Harper, J. W., & Elledge, S. J. (1995) · Science · doi:10.1126/science.7863329 · Cited by 1,032 · see citing works
Teratocarcinomas and embryonic stem cells: A practical approach
Krumlauf, R. K. (1987) · Trends in Genetics · doi:10.1016/0168-9525(87)90286-1 · Cited by 782 · see citing works
Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit
Gu, Y., Turck, C. W., & Morgan, D. O. (1993) · Nature · doi:10.1038/366707a0 · Cited by 771 · see citing works
Merritt, A. J., Potten, C. S., Kemp, C. J., Hickman, J. A., Balmain, A., Lane, D. P., & Hall, P. A. (1994) · PubMed · Cited by 560 · see citing works
Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.Preprint
Xiong, Y., Zhang, H., & Beach, D. (1993) · Genes & Development · doi:10.1101/gad.7.8.1572 · Cited by 507 · see citing works
Self-citationHermiston, M. L., & Gordon, J. I. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.129.2.489 · Cited by 415 · see citing works
Self-citationA Comprehensive Study of the Radiobiological Response of the Murine (BDF1) Small Intestine
Potten, C. S. (1990) · International Journal of Radiation Biology · doi:10.1080/09553009014552281 · Cited by 272 · see citing works
Clarke, A. R., Gledhill, S., Ml, H., Bird, C. C., & Wyllie, A. (1994) · PubMed · Cited by 267 · see citing works
Differentiation and self-renewal in the mouse gastrointestinal epithelium
Gordon, J. I., & Hermiston, M. L. (1994) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(94)90047-7 · Cited by 258 · see citing works
Self-citationPolymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer.
Li, Y., Laurent‐Puig, P., Salmon, R. J., Thomas, G. D., & Hamelin, R. (1995) · PubMed · Cited by 86 · see citing works
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CDK inhibitors: positive and negative regulators of G1-phase progression
Sherr, C. J., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.12.1501 · Cited by 6,115 · see citing works
“…overexpression of catalytically inactive CDK4 can also reverse a cell cycle block imposed by p16 (Koh et al. 1995; Jiang et al. 1998) or by p53 (Latham et al. 1996), which arrests cells in G1 by inducing p21 (El-Deiry et al. 1993; Dulic et al. 1994; Brugarolas et al. 1995; Deng et al. 1995).”
BackgroundSherr, C. J. (1996) · Science · doi:10.1126/science.274.5293.1672 · Cited by 5,379 · 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 · see citing works
“Primary human Sciences) for human p21; an affinity-purified rabbit polyclonal antibody (Brugarolas et al., 1995) for rodent p21; DCS-50 (Novocastra)and mouse fibroblasts were subcultured 1:4 upon reaching conflu- ence; each passage was considered two PDLs. for human p16; M-156 (Santa Cruz) for…”
MethodSelf-citationRequirement for p53 and p21 to Sustain G <sub>2</sub> Arrest After DNA Damage
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., & Vogelstein, B. (1998) · Science · doi:10.1126/science.282.5393.1497 · Cited by 2,803 · see citing works
A microRNA component of the p53 tumour suppressor network
He, L., He, X., Lim, L. P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus, J., Ridzon, D., et al. (2007) · Nature · doi:10.1038/nature05939 · Cited by 2,692 · see citing works
Self-citationp21 in cancer: Intricate networks and multiple activities
Abbas, T., & Dutta, A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2657 · Cited by 2,712 · see citing works
“Among these, the small 165 amino acid protein p21 (also known as p21 WAF1/Cip1 ) mediates p53 -dependent G1 growth arres”
Backgroundp53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
PUMA, a Novel Proapoptotic Gene, Is Induced by p53
Nakano, K., & Vousden, K. H. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00214-3 · Cited by 2,315 · see citing works
“…and loss of p21WAF1/CIP1 profoundly reduces the ability of cells to undergo this responseThe p53 tumor-suppressor protein functions to inhibit the growth of stressed or abnormal cells, and so prevent following p53 activation (Brugarolas et al., 1995; Deng et al., 1995; Waldman et al., 1995).”
BackgroundA Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response
Huarte, M., Guttman, M., Feldser, D., Garber, M., Koziol, M. J., Kenzelmann-Broz, D., Khalil, A. M., Zuk, O., Amit, I., Rabani, M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.040 · Cited by 2,053 · see citing works
“Cell-cycle analysis was performed as described (Brugarolas et al., 1995).”
Self-citationCell Cycle Checkpoints: Preventing an Identity Crisis
Elledge, S. J. (1996) · Science · doi:10.1126/science.274.5293.1664 · Cited by 2,047 · see citing works
Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., SHISHIDO, N., Horii, I., Loh, D. Y., & Nakayama, K. (1996) · Cell · doi:10.1016/s0092-8674(00)81237-4 · Cited by 1,548 · see citing works
Programmed cell senescence during mammalian embryonic development
Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.019 · Cited by 1,428 · see citing works
Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia
Barlow, C., Hirotsune, S., Paylor, R. E., Liyanage, M., Eckhaus, M., Collins, F. S., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D. A., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80086-0 · Cited by 1,450 · see citing works
Fero, M. L., Rivkin, M. J., Tasch, M., Porter, P. L., Carow, C. E., Firpo, E. J., Polyák, K., Tsai, L., Broudy, V. C., Perlmutter, R. M., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81239-8 · Cited by 1,459 · see citing works
New functional activities for the p21 family of CDK inhibitors.
LaBaer, J., Garrett, M. D., Stevenson, L. F., Slingerland, J. M., Sandhu, C., Chou, H. S., Fattaey, A., & Harlow, E. (1997) · Genes & Development · doi:10.1101/gad.11.7.847 · Cited by 1,402 · see citing works
“Although p21 can assemble complexes in vitro and in vivo, the observation that p21 nullizygous mice undergo normal development and are fully fertile shows that p21 is not required for normal cell cycle function (Brugarolas et al. 1995; Deng et al. 1995).”
BackgroundUnravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,389 · see citing works
Hematopoietic Stem Cell Quiescence Maintained by p21 <sup>cip1/waf1</sup>
Cheng, T., Rodrigues, N., Shen, H., Yang, Y.-G., Dombkowski, D., Sykes, M., & Scadden, D. T. (2000) · Science · doi:10.1126/science.287.5459.1804 · Cited by 1,339 · see citing works
Linkage of ATM to Cell Cycle Regulation by the Chk2 Protein Kinase
Matsuoka, S. (1998) · Science · doi:10.1126/science.282.5395.1893 · Cited by 1,322 · see citing works
Sanchez, Y., Wong, C., Thoma, R. S., Richman, R., Wu, Z., Piwnica-Worms, H., & Elledge, S. J. (1997) · Science · doi:10.1126/science.277.5331.1497 · Cited by 1,320 · see citing works
The Cell–Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression
Chen, J. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026104 · Cited by 1,222 · see citing works
“However, p21-null cells are not completely defective for G1 arrest, suggesting that other p53 target genes also contribute to the growth arrest (Brugarolas et al. 1995). p53 activation also arrests cells at the G2/M phases.”
BackgroundIs a p53-Regulated Inhibitor of G2/M Progression
Hermeking, H., Lengauer, C., Polyak, K., He, T.-C., Zhang, L., Thiagalingam, S., Kinzler, K. W., & Vogelstein, B. (1997) · Molecular Cell · doi:10.1016/s1097-2765(00)80002-7 · Cited by 1,251 · see citing works
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · see citing works
“Although mice deficient in p21 are described as being developmentally normal (Brugarolas et al., 1995; Deng et al., 1995), we sought to examine this more closely and assess whether p21 deficiency might cause defects in embryonic senescence.”
BackgroundStott, 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
“Through its ability to inhibit G1-specific cyclin-dependent kinase complexes and to bind to proliferating cell nuclear antigen (PCNA), p21CIP1 is believed to be a major executor of the p53-dependent cell cycle arrest that occurs in response to DNA damage (Brugarolas et al., 1995; Deng et al., 1995; reviewed in Sherr a…”
BackgroundCheng, M., Olivier, P., Diehl, J. A., Fero, M., Roussel, M. F., Roberts, J. M., & Sherr, C. J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1571 · Cited by 1,142 · see citing works
“…fact that p21 nullizygous mice undergo normal development and do not seem to have a significant deficiency in cyclin D-dependent kinase function (Brugarolas et al., 1995; Deng et al., 1995) leaves open the question of whether the CKIs are normal physiological regulators of cyclin D–CDK assembly.”
BackgroundP53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080 · see citing works
A large-scale RNAi screen in human cells identifies new components of the p53 pathway
Berns, K., Hijmans, E. M., Mullenders, J., Brummelkamp, T. R., Velds, A., Heimerikx, M., Kerkhoven, R. M., Madiredjo, M., Nijkamp, W., Weigelt, B., et al. (2004) · Nature Cell Biology · doi:10.1038/nature02371 · Cited by 1,059 · see citing works
Disruption of p53 in human cancer cells alters the responses to therapeutic agents.
Bunz, F., Hwang, P. M., Torrance, C., Waldman, T., Zhang, Y., Dillehay, L., Williams, J., Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6863 · Cited by 1,044 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
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
Self-citationChin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · see citing works
“Consistent with the established role of p53 and 21 atrophy Normal p21 in mediating a biphasic arrest in response to 21 atrophy 11 atrophy DNA damage signals (Brugarolas et al., 1995; Deng et 31 atrophy 21 atrophy al., 1995; Bunz et al., 1998) loss of p53 abrogated this Normal 21 atrophy”
BackgroundThe role of the cyclin-dependent kinase inhibitor p21 in apoptosis.
Gartel, A. L., & Tyner, A. L. (2002) · PubMed · Cited by 924 · see citing works
A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage
Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., & Nakamura, Y. (2000) · Nature · doi:10.1038/35003506 · Cited by 904 · see citing works
p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
Müller, M., Wilder, S., Bannasch, D., Israeli, D., Lehlbach, K., Li-Weber, M., Friedman, S. L., Galle, P. R., Stremmel, W., Oren, M., et al. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.11.2033 · Cited by 878 · see citing works
Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro
Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K., & Elledge, S. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.190030497 · Cited by 830 · see citing works
The Mammalian Ovary from Genesis to Revelation
Edson, M. A., Nagaraja, A. K., & Matzuk, M. M. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0012 · Cited by 828 · see citing works
“Although Cdkn1a / female mice are fertile (394, 395), in contrast to observations in Cdkn1b / mice, their ovaries are not enlarged compared with wild-type ovaries.”
Lost in Transcription: p21 Repression, Mechanisms, and Consequences
Gartel, A. L., & Radhakrishnan, S. K. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3995 · Cited by 819 · see citing works
“Although it was suggested earlier that p21 knockout mice undergo normal development (16), a more recent”
BackgroundSenescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
Regulation ofp53downstream genes
El‐Deiry, W. S. (1998) · Seminars in Cancer Biology · doi:10.1006/scbi.1998.0097 · Cited by 797 · see citing works
Rapid Destruction of Human Cdc25A in Response to DNA Damage
Mailand, N., Falck, J., Lukas, C., Syljuåsen, R. G., Welcker, M., Bartek, J., & Lukas, J. (2000) · Science · doi:10.1126/science.288.5470.1425 · Cited by 787 · see citing works
Chen, X., Ko, L. J., Jayaraman, L., & Prives, C. (1996) · Genes & Development · doi:10.1101/gad.10.19.2438 · Cited by 735 · see citing works
“This observation is consistent wi th the results of Brugarolas et al. (1995] and Deng et al.”
ResultNiculescu, A. B., Chen, X., Smeets, M. F. M. A., Hengst, L., Prives, C. L., & Reed, S. I. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.1.629 · Cited by 725 · see citing works
“However, the p53-dependent G1 arrest response to DNA damage is at least partially defective in fibroblasts from p21-nullizygous mice (4), supporting the idea that this is one of the critical functions of p21 that cannot be completely compensated by other modes of regulation.”
BackgroundLim, D., & Hasty, P. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.12.7133 · Cited by 687 · see citing works
“p53 initiates the transcription of genes that regulate the cell cycle or stimulate programmed cell death, including p21 (13, 18, 21, 31, 87) and BAX (52), and is critical for the response to gamma radiation-induced DNA damage (20, 47, 48).”
BackgroundHarris, C. C. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.20.1442 · Cited by 682 · see citing works
The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.
Hakem, R., de la Pompa, J. L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81302-1 · Cited by 680 · see citing works
Transcriptional Regulation of the p21(WAF1/CIP1)Gene
Gartel, A. L., & Tyner, A. L. (1999) · Experimental Cell Research · doi:10.1006/excr.1998.4319 · Cited by 664 · see citing works
Twenty years of p53 research: structural and functional aspects of the p53 protein
May, P., & May, E. (1999) · Oncogene · doi:10.1038/sj.onc.1203285 · Cited by 663 · see citing works
“…have shown that embryonic ®broblasts obtained from p217/7 mice are only partially defective in their ability to undergo G1 arrest following exposure to IR (Deng et al., 1995; Brugarolas et al., 1995) suggesting that another gene product transactivated by p53 contributes to a complete response.”
BackgroundThe P53 pathway: what questions remain to be explored?
Levine, A. J., Hu, W., & Feng, Z. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401910 · Cited by 654 · see citing works
A Proinflammatory Cytokine Inhibits P53 Tumor Suppressor Activity
Hudson, J. D., Shoaibi, M. A., Maestro, R., Carnero, A., Hannon, G. J., & Beach, D. H. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.10.1375 · Cited by 649 · see citing works
“nology), MDM2 (SMP-14; Santa Cruz Biotechnology), Bax (BAX D p21; Santa Cruz Biotechnology), or p21 (23) followed by a horseradish peroxidase–conjugated anti–mouse antibody, and”
BackgroundSelf-citationSUMO‐1 modification activates the transcriptional response of p53
Rodríguez, M. S., Desterro, J. M. P., Laı́n, S., Midgley, C., Lane, D. P., & Hay, R. T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.22.6455 · Cited by 639 · see citing works
“This accumulation of p53 is responsible for the increased transcription of cellular genes, the products of which are associated with cell cycle arrest (p21Waf1Cip1) or apoptosis (Bax), and constitute a significant part of the p53 response (Lu and Lane, 1993; Brugarolas et al., 1995; Waldman et al., 1995; McCurrach et…”
BackgroundInvolvement of Brca2 in DNA Repair
Patel, K. J., Yu, V. P. C. C., Lee, H., Corcoran, A. E., Thistlethwaite, F. C., Evans, M. J., Colledge, W. H., Friedman, L. S., Ponder, B. A. J., & Venkitaraman, A. R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80035-0 · Cited by 631 · see citing works
The cellular response to p53: the decision between life and death
Sionov, R. V., & Haupt, Y. (1999) · Oncogene · doi:10.1038/sj.onc.1203130 · Cited by 600 · see citing works
“Indeed, ®broblasts de®cient in p21 are impaired in IR-induced growth arrest (Brugarolas et al., 1995; Deng et al., 1995), and p21-de®cient normal ®broblasts and tumor cells are more sensitive to p53-induced apoptosis (Gorospe et al., 1997; Polyak et al., 1996).”
BackgroundSage, 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
“Control cells were plated at 106 cells per 10-cm dish, and the day after, they were irradiated with a dose of 5 Grays (Brugarolas et al. 1995) or treated with 0.2 µg/mL of doxorubicin (Sigma; Attardi et al. 2000).”
BackgroundMethodInfluentialSelf-citationRegulation of G1 cyclin-dependent kinases in the mammalian cell cycle
Ekholm, S. V., & Reed, S. I. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00151-4 · Cited by 587 · see citing works
Tumor Suppressive Functions of p53Preprint
Zilfou, J. T., & Lowe, S. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001883 · Cited by 572 · see citing works
“Targeted disruption of the p21 gene has been shown to compromise the G1/S checkpoint in MEFs and significantly extend their lifespan (Brugarolas et al. 1995; Deng et al. 1995).”
BackgroundStructure of the p53 Tumor Suppressor Bound to the Ankyrin and SH3 Domains of 53BP2
Gorina, S. S., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.1001 · Cited by 571 · see citing works
microRNAs join the p53 network — another piece in the tumour-suppression puzzle
He, L., He, X., Lowe, S. W., & Hannon, G. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2232 · Cited by 546 · see citing works
“Moreover, genetic studies of p53-regulated protein-coding genes had not yet provided a complete picture of how regulation of these targets might lead to commonly observed effects of p53 activation, such as G1 cell-cycle arrest or apoptosis, in all tissue setting”
BackgroundSelf-citationHinnebusch, B. F., Meng, S., Wu, J. T., Archer, S. Y., & Hodin, R. A. (2002) · Journal of Nutrition · doi:10.1093/jn/132.5.1012 · Cited by 546 · 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
p21 WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells
Archer, S. Y., Meng, S., Shei, A., & Hodin, R. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.12.6791 · Cited by 534 · see citing works
Fiscella, M., Zhang, H., Fan, S., Sakaguchi, K., Shen, S., Mercer, W. E., Woude, G. F. V., O'Connor, P. M., & Appella, E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6048 · Cited by 527 · see citing works
Bernstein, C. (2002) · Mutation Research/Reviews in Mutation Research · doi:10.1016/s1383-5742(02)00009-1 · Cited by 527 · see citing works
“regulation of p21 leads to cell cycle arrest by inhibiting cyclin-dependent kinase function [201] and cyclin G has pro-apoptotic activity[202].”
BackgroundHeme oxygenase-1 protects against vascular constriction and proliferation
Duckers, H. J., Boehm, M., True, A. L., Yet, S., San, H., Park, J. L., Webb, R. C., Lee, M.-E., Nabel, G. J., & Nabel, E. G. (2001) · Nature Medicine · doi:10.1038/89068 · Cited by 524 · see citing works
The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme
Tell, G., Quadrifoglio, F., Tiribelli, C., & Kelley, M. R. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2194 · Cited by 515 · see citing works
“126, and 35, 67, 88), other data underlined its potential role in controlling proapoptotic functions through p53-mediated activation of p21 (38, 54, 117), leading to the arrest of cell cycle by inhibiting cyclin-dependent kinase function (11), and cyclin G, having pro-apoptotic activity (97).”
Koyama, H., Raines, E. W., Bornfeldt, K., Roberts, J. M., & Ross, R. (1996) · Cell · doi:10.1016/s0092-8674(00)81801-2 · Cited by 514 · see citing works
Funk, J. O., Waga, S., Harry, J. B., Espling, E., Stillman, B., & Galloway, D. A. (1997) · Genes & Development · doi:10.1101/gad.11.16.2090 · Cited by 514 · see citing works
p21: a two-faced genome guardian.
Georgakilas, A. G., Martin, O. A., & Bonner, W. M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.02.001 · Cited by 489 · see citing works
Genomic instability in Gadd45a-deficient mice
Hollander, M. C., Sheikh, M. S., Bulavin, D. V., Lundgren, K., Augeri-Henmueller, L., Shehee, R., Molinaro, T. A., Kim, K. E., Tolosa, E., Ashwell, J. D., et al. (1999) · Nature Genetics · doi:10.1038/13802 · Cited by 507 · see citing works
“Athough p21 Cip1/Waf1 (encoded by Cdkn1a ) appears to be the major effector of the p53-mediated G 1 checkpoint and has also been implicated in other checkpoints, Cdkn1a –/– mice do not exhibit features of genomic instability seen in Trp53 –/– mic”
BackgroundHuang, M., Zhou, Z., & Elledge, S. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81601-3 · Cited by 499 · see citing works
Mitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 502 · see citing works
“While p21Waf1 is key to the ability of p53 to induce growth arrest (352), there are numerous downstream effectors of p53-induced apoptosis (350), including p53 itself (353, 354).”
BackgroundCharacterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption
Lanni, J. S., & Jacks, T. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.2.1055 · Cited by 493 · see citing works
“This arrest is mediated in large part by p21, a transcriptional target of the p53 protein which inhibits CDKs and prevents phosphorylation of the Rb protein, a requirement for S phase entry (2, 7).”
BackgroundInfluentialSelf-citationYan, Y., Frisén, J., Lee, M., Massagué, J., & Barbacid, M. (1997) · Genes & Development · doi:10.1101/gad.11.8.973 · Cited by 491 · see citing works
p53 in growth control and neoplasia
Gottlieb, T. M., & Oren, M. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00019-c · Cited by 481 · see citing works
CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair
Esashi, F., Christ, N., Gannon, J., Liu, Y., Hunt, T., Jasin, M., & West, S. C. (2005) · Nature · doi:10.1038/nature03404 · Cited by 473 · see citing works
“ATM transduces the DNA damage signal to p53, leading to the transcriptional activation of p21 that inhibits CDK activit”
Backgroundp21WAF1/Cip1: more than a break to the cell cycle?
Dotto, G. P. (2000) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(00)00019-6 · Cited by 474 · see citing works
p21 and p27: roles in carcinogenesis and drug resistance
Abukhdeir, A. M., & Park, B. H. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000744 · Cited by 463 · 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
“We therefore compared the effects of RafAR on the proliferation of MEFs from wild-type mice to its effects on the proliferation of MEFs from mice in which the p21 (4), cyclin D1 (23), or p53 (45) gene is ablated by homologous recombination.”
BackgroundGenetic determinants of p53-induced apoptosis and growth arrest.Preprint
Polyák, K., Waldman, T. A., He, T., Kinzler, K. W., & Vogelstein, B. (1996) · Genes & Development · doi:10.1101/gad.10.15.1945 · Cited by 458 · see citing works
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
“passaging of primary cell cultures as well as in response to cellular stress and acts to arrest cell-cycle progression at the G1/S checkpoint (Deng et al., 1995; Brugarolas et al., 1995).”
BackgroundMethodInfluentialSelf-citationRoninson, I. B. (2002) · Cancer Letters · doi:10.1016/s0304-3835(01)00847-3 · Cited by 443 · see citing works
Rouault, J.-P., Falette, N., Guéhenneux, F., Guillot, C., Rimokh, R., Wang, Q., Berthet, C., Moyret-Lalle, C., Savatier, P., Pain, B., et al. (1996) · Nature Genetics · doi:10.1038/ng1296-482 · Cited by 434 · see citing works
Chk2‐deficient mice exhibit radioresistance and defective p53‐mediated transcription
Takai, H., Naka, K., Okada, Y., Watanabe, M., Harada, N., Saito, S., Anderson, C. W., Appella, E., Nakanishi, M., Suzuki, H., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf506 · Cited by 435 · see citing works
Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response
Cazzalini, O., Scovassi, A. I., Savio, M., Stivala, L. A., & Prosperi, E. (2010) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2010.01.009 · Cited by 430 · see citing works
“Additionally, mouse embryonic fibroblasts (MEFs) obtained fromp21-nullmice fail to arrest in G1 phase in response to DNA damage [25,26].”
BackgroundCell-cycle inhibitors: three families united by a common cause
Vidal, A., & Koff, A. (2000) · Gene · doi:10.1016/s0378-1119(00)00092-5 · Cited by 429 · see citing works
Homologous recombinational repair of DNA ensures mammalian chromosome stability
Thompson, L. H., & Schild, D. (2001) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(01)00115-4 · Cited by 426 · see citing works
Senescence-associated inflammatory responses: aging and cancer perspectives
Lasry, A., & Ben-Neriah, Y. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.009 · Cited by 408 · see citing works
An overview of Cdk1-controlled targets and processes
Enserink, J. M., & Kolodner, R. D. (2010) · Cell Division · doi:10.1186/1747-1028-5-11 · Cited by 409 · see citing works
“One key inhibitor of the cell cycle is p53, which blocks the cell cycle by inhibiting CDK activity in several ways, one of which is inducing the transcription of p21 [572,573], which binds and inactivates cyclin-CDK complexes.”
BackgroundDannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
“…was determined by incubating MEFs with 5-Bromodeoxyuridine (0.3 µg/mL) plus 5-Fluoro-5deoxyuridine (0.03 µg/mL) for 5 h. Cells were collected and resuspended in 70% alcohol at 4°C, stained with DAKO mouse anti-BrdU antibody, and prepared for FACS analysis as described in Brugarolas et al. (1995).”
BackgroundMethodInfluentialMechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
“Surprisingly, developmental senescence is not required for embryogenesis because embryos lacking p21 show minimal or no developmental defects [56].”
BackgroundDual roles of ATM in the cellular response to radiation and in cell growth control.Preprint
Xu, Y., & Baltimore, D. (1996) · Genes & Development · doi:10.1101/gad.10.19.2401 · Cited by 402 · see citing works
Regulation of Chromosome Replication
Kelly, T. J., & Brown, G. W. (2000) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.69.1.829 · Cited by 399 · see citing works
Cdk inhibitors in development and cancer
Harper, J. W., & Elledge, S. J. (1996) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(96)90011-8 · Cited by 400 · see citing works
PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 familyPreprint
Attardi, L. D., Reczek, E. E., Cosmas, C., Demicco, E. G., McCurrach, M. E., Lowe, S. W., & Jacks, T. (2000) · Genes & Development · doi:10.1101/gad.14.6.704 · Cited by 394 · see citing works
“Dishes of both treated and untreated wild-type and p53−/− MEFs were collected after 18 hr of doxorubicin treatment for FACS analysis to verify a p53-dependent G1 arrest, as described previously (Brugarolas et al. 1995).”
MethodSelf-citationReeler: new tales on an old mutant mouse
D’Arcangelo, G., & Curran, T. (1998) · BioEssays · doi:10.1002/(sici)1521-1878(199803)20:3 · Cited by 156 · see citing works
The retinoblastoma protein pathway and the restriction point
Bartek, J., Bártková, J., & Lukas, J. (1996) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(96)80081-0 · Cited by 388 · see citing works
Cell-cycle arrest versus cell death in cancer therapy
Waldman, T. A., Zhang, Y., Dillehay, L. E., Yu, J., Kinzler, K. W., Vogelstein, B., & Williams, J. (1997) · Nature Medicine · doi:10.1038/nm0997-1034 · Cited by 388 · see citing works
Inhibition of p21‐mediated ROS accumulation can rescue p21‐induced senescence
Macip, S., Igarashi, M., Fang, L., Chen, A., Pan, Z., Lee, S. W., & Aaronson, S. A. (2002) · The EMBO Journal · doi:10.1093/emboj/21.9.2180 · Cited by 374 · see citing works
Xu, X., Qiao, W., Linke, S. P., Cao, L., Li, W., Furth, P. A., Harris, C. C., & Deng, C. (2001) · Nature Genetics · doi:10.1038/90108 · Cited by 372 · see citing works
“nature genetics • volume 28 • july 2001 271 (5-6) early embryonic lethality by p53 or p21 null mutation.”
BackgroundMcCurrach, M. E., Connor, T. M. F., Knudson, C. M., Korsmeyer, S. J., & Lowe, S. W. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.6.2345 · Cited by 368 · see citing works
Abbas, T., Sivaprasad, U., Terai, K., Amador, V., Pagano, M., & Dutta, A. (2008) · Genes & Development · doi:10.1101/gad.1676108 · Cited by 367 · see citing works
“p21 inhibits the kinase activity of Cdk2, thereby preventing progression into or through the S phase of the cell cycle (Brugarolas et al. 1995).”
BackgroundKolluri, S. K., Weiss, C., Koff, A., & Göttlicher, M. (1999) · Genes & Development · doi:10.1101/gad.13.13.1742 · Cited by 364 · see citing works
“Yet, p21-deficient cells are only partially impaired in their capacity to arrest proliferation on DNA damage (Brugarolas et al. 1995; Deng et al. 1995) presumably because of alternate pathways that allow even p21-deficient cells to inhibit proliferation on damage.”
Background
- Authors
- Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Washington University in St. Louis (US)
- Venue
- Nature
- Published
- 1995-10
- Volume
- 377
- Issue
- 6549
- Pages
- 552-557
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1969385456
- Cited by
- 1,242
- References
- 24
- Citations by year
- 2026: 10 · 2025: 5 · 2024: 13 · 2023: 29 · 2022: 21 · 2021: 29 · 2020: 22 · 2019: 27 · 2018: 28 · 2017: 31 · 2016: 24 · 2015: 26 · 2014: 26 · 2013: 29 · 2012: 41
- FWCI
- 33.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- p21, cell cycle arrest, radiation-induced DNA damage, G1 cell cycle arrest, cyclin-dependent kinases, PCNA, p53, apoptosis, chimeric mice, intestinal epithelial differentiation, mouse embryonic fibroblasts, cellular senescence
- MeSH terms
- Animals, Cell Cycle, Cell Differentiation, Cell Division, Cell Line, Cells, Cultured, Chimera, Enzyme Inhibitors, Gamma Rays, Intestine, Small, Mice, Inbred C57BL, Tumor Suppressor Protein p53, Cyclins, Apoptosis, Protein Serine-Threonine Kinases, Gene Targeting, Proliferating Cell Nuclear Antigen, Cyclin-Dependent Kinases, CDC2-CDC28 Kinases, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase 2, Mice
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