Cited by 1,242Cancer-related Molecular PathwaysDNA Repair MechanismsTelomeres, Telomerase, and Senescence

The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.

Radiation-induced cell cycle arrest compromised by p21 deficiency

Brugarolas, James, Chandrasekaran, Chitra, Gordon, Jeffrey I., Beach, David, Jacks, Tyler, Hannon, Gregory J.·1995·Nature

DOI 10.1038/377552a0

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/377552a0

Cites

24 of 24 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?

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
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
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
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
Self-citation
A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Kastan, 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
Self-citation
Altering the Genome by Homologous Recombination
Capecchi, M. R. (1989) · Science · doi:10.1126/science.2660260 · Cited by 2,037
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
Self-citation
Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes
Mansour, S. L., Thomas, K. R., & Capecchi, M. R. (1988) · Nature · doi:10.1038/336348a0 · Cited by 1,683
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
Self-citation
p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest
Dulić, 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

Flagged first, then by citations

Show all 24 references

Research works printed but not linked: 3

Merritt, A. J. et al. Cancer Res. 54, 614–617 (1994).
Clarke, A. R., Gledhill, S., Hooper, M. L., Bird, C. C. & Wyllie, A. H. Oncogene 9, 1767–1773 (1994).
Li, Y.-J., Laurent-Puig, P., Salmon, R. J., Thomas, G. & Hamelin, R. Oncogene 10, 599–601 (1994).

Sorted by citations

Items 501–600 of 1,000

Transcriptional Regulation of the Human DNA Polymerase δ Catalytic Subunit Gene POLD1 by p53 Tumor Suppressor and Sp1
Li, B., & Lee, M. Y. W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101167200 · Cited by 65
Identification of Tcf-4 as a transcriptional target of p53 signalling
Rother, K., Johne, C., Spiesbach, K., Haugwitz, U., Tschöp, K., Wasner, M., Klein‐Hitpaß, L., Möröy, T., Mössner, J., & Engeland, K. (2004) · Oncogene · doi:10.1038/sj.onc.1207464 · Cited by 65
“…target for p53-dependent transcriptional activation is the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (el-Deiry et al., 1993). p53 is thought to exert its function in G1 checkpoint control mainly through increased expression from the p21 gene (Brugarolas et al., 1995; Deng et al., 1995).”
Background
Cell-cycle regulation in immunity, tolerance and autoimmunity
Balomenos, D., & Martínez‐A, C. (2000) · Immunology Today · doi:10.1016/s0167-5699(00)01748-5 · Cited by 64
Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron
Kramer, J. L., Baltathakis, I., Alcantara, O., & Boldt, D. H. (2002) · British Journal of Haematology · doi:10.1046/j.1365-2141.2002.03498.x · Cited by 64
“Paradoxically, it has been noted that peripheral blood counts in p21–/– mice are normal (Brugarolas et al, 1995; Deng et al, 1995; Cheng et al, 2000).”
Background
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
Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy
Lee, A. K., Pan, D., Bao, X., Hu, M., Li, F., & Li, C. (2020) · Radiation Research · doi:10.1667/rade-20-00013 · Cited by 69
Inhibition of Nuclear Pore Complex Formation Selectively Induces Cancer Cell Death
Sakuma, S., Raı́ces, M., Borlido, J., Guglielmi, V., Zhu, E. Y. S., & D’Angelo, M. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0581 · Cited by 60
“Both treatments resulted in strong downregulation of NUP160 expression levels, decreased NPC numbers and increased p21 (CDKN1A) expression, a marker of G1/S cell cycle arrest (26,27) (Supplementary Fig 3A and B).”
Background
Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer
Bauer, J. I., Özden, Ö., Akagi, N., Carroll, T. P., Principe, D. R., Staudacher, J. J., Spehlmann, M. E., Eckmann, L., Grippo, P. J., & Jung, B. H. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0456-4 · Cited by 63
“Earlier studies support the view that p21 suppresses tumors by promoting cell cycle arrest in response to various stimuli [44, 45].”
Background
Invited Review: Effect of oxygen deprivation on cell cycle activity: a profile of delay and arrest
Douglas, R. M., & Haddad, G. G. (2003) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01029.2002 · Cited by 65
AMF1 (GPS2) Modulates p53 Transactivation
Peng, Y., Kuo, F., Breiding, D. E., Wang, Y., Mansur, C. P., & Androphy, E. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.17.5913-5924.2001 · Cited by 62
“activity appears to be dispensable for apoptosis (2, 9).”
BackgroundResult
Inosine-5′-Monophosphate Dehydrogenase Is a Rate-determining Factor for p53-dependent Growth Regulation
Liu, Y., Bohn, S. A., & Sherley, J. L. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.1.15 · Cited by 63
“Studies with cells from mice with a germline disruption of the waf1 gene indicate that the growth suppression function of the waf1 protein is limited to conditions of DNA damage (Brugarolas et al., 1995; Deng et al., 1995).”
Background
Analysis of Cyclin D3-cdk4 Complexes in Fibroblasts Expressing and Lacking p27 kip1 and p21 cip1
Bagui, T. K., Jackson, R. J., Agrawal, D., & Pledger, W. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.23.8748-8757.2000 · Cited by 63
“Two mouse models were used to test this premise: one in which the entire coding regions of p27 and p21 were eliminated (termed p27/p21) and the other in which the entire coding region of p21 and the N-terminal cyclin-cdk binding domain of p27 (termed p27N/p21) were deleted (4, 18, 24).”
MethodInfluential
Identification of Breast Cancer Inhibitors Specific for G Protein‐Coupled Estrogen Receptor (GPER)‐Expressing Cells
Aiello, F., Carullo, G., Giordano, F., Spina, E., Nigro, A., Garofalo, A., Tassini, S., Costantino, G., Vincetti, P., Bruno, A., et al. (2017) · ChemMedChem · doi:10.1002/cmdc.201700145 · Cited by 62
Naftopidil, a selective α‐1 adrenoceptor antagonist, inhibits growth of human prostate cancer cells by G1 cell cycle arrest
Kanda, H., Ishii, K., Ogura, Y., Imamura, T., Kanai, M., Arima, K., & Sugimura, Y. (2007) · International Journal of Cancer · doi:10.1002/ijc.23095 · Cited by 62
Induction of genetic instability by gain-of-function p53 cancer mutants
Xu, Y. (2008) · Oncogene · doi:10.1038/sj.onc.1211023 · Cited by 63
“…transcriptional activity of p53 is critical for its functions. p21 and 14–3–3s, both transcriptional targets of p53, are required for mediating p53-dependent cell cycle G1/S and G2/M cell cycle checkpoints (el-Deiry et al., 1993; Brugarolas et al., 1995; Deng et al., 1995; Hermeking et al., 1997).”
Background
Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level
Hubert, A., Paris, S., Piret, J., Ninane, N., Raes, M. J., & Michiels, C. (2006) · Journal of Cell Science · doi:10.1242/jcs.03069 · Cited by 65
“The cyclindependent kinase inhibitor, p21waf-1, appears to be the major effector of p53-mediated cell-cycle arrest (Brugarolas et al., 1995; Waldman et al., 1995) whereas the transcriptional induction of Bax largely contributes to p53-mediated cell death (Miyashita et al., 1994).”
Chemokine receptor CXCR 2 is transactivated by p53 and induces p38‐mediated cellular senescence in response to DNA damage
Guo, H., Liu, Z., Xu, B., Hu, H., Wei, Z., Liu, Q., Zhang, X., Ding, X., Wang, Y., Zhao, M., et al. (2013) · Aging Cell · doi:10.1111/acel.12138 · Cited by 63
“, 2007), only a few p53 target genes, namely p21, PAI-1, PML, and E2F7, are known to mechanistically contribute to cellular senescence (Brugarolas et al., 1995; Brown et al., 1997; Kagawa et al., 1999; Wang et al., 1999; de Stanchina et al., 2004; Kortlever et al., 2006; Aksoy et al., 2012; Carvajal et al., 2012).”
BackgroundInfluential
Mdm2 Is Required for Inhibition of Cdk2 Activity by p21, Thereby Contributing to p53-Dependent Cell Cycle Arrest
Giono, L. E., & Manfredi, J. J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01967-06 · Cited by 62
“Moreover, p21 has been shown to be both sufficient and required for proper G1 arrest (5, 12, 38, 47) through binding and inhibition of cdk complexes (6, 18).”
Background
A Single Recombinant Adenovirus Expressing p53 and p21-targeting Artificial microRNAs Efficiently Induces Apoptosis in Human Cancer Cells
Idogawa, M., Sasaki, Y., Suzuki, H., Mita, H., Imai, K., Shinomura, Y., & Tokino, T. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2396 · Cited by 62
Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers
Lhuillier, C., Vanpouille‐Box, C., Galluzzi, L., Formenti, S. C., & Demaria, S. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.12.007 · Cited by 63
“Moreover, even though the molecular pathways linking RT-driven DNA damage to cellular senescence or RCD have been extensively characterized in preclinical models [49, 50] and at least in part confirmed in the clinical, the actual predictive value of other components of the DDR machinery for cancer patients remains unk…”
Background
Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties.
Bearss, D. J., Lee, R. J., Troyer, D. A., Pestell, R. G., & Windle, J. J. (2002) · PubMed · Cited by 62
A Balancing Act: p53 Activity from Tumor Suppression to Pathology and Therapeutic Implications
Wang, M., & Attardi, L. D. (2021) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-042320-025840 · Cited by 61
Loss of p21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells despite Unchecked Apoptosis
Willenbring, H., Sharma, A. D., Vogel, A., Lee, A. Y., Rothfuß, A., Wang, Z., Finegold, M. J., & Grompe, M. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.004 · Cited by 61
“, 1993) and B6;129S2-Cdkn1a/J (Brugarolas et al., 1995) (The Jackson Laboratory) mice were crossed to generate Fah / ,p21 breeders from which all Fah / and Fah / ,p21 / animals used in these studies were derived.”
p21WAF1 regulates anchorage-independent growth of HCT116 colon carcinoma cells via E-cadherin expression.
Mueller, S., Cadenas, E., & Schönthal, A. H. (2000) · PubMed · Cited by 61
Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels
Nawrocki, S. T., Carew, J. S., Douglas, L., Cleveland, J. L., Humphreys, R. C., & Houghton, J. A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0812 · Cited by 61
“A hallmark of HDAC inhibitor treatment is a dramatic up-regulation of the CDK inhibitor p21(23), which is also a transcription target induced by the tumor suppressor p53 ( 24 ).”
Background
Revisiting Cationic Phosphorus Dendrimers as a Nonviral Vector for Optimized Gene Delivery Toward Cancer Therapy Applications
Chen, L., Li, J., Fan, Y., Qiu, J., Cao, L., Laurent, R., Mignani, S. M., Caminade, A., Majoral, J., & Shi, X. (2020) · Biomacromolecules · doi:10.1021/acs.biomac.0c00458 · Cited by 61
APE1/Ref-1 regulates PTEN expression mediated by Egr-1
Fantini, D., Fantini, D., Vascotto, C., Deganuto, M., Bivi, N., Gustincich, S., Marcon, G., Quadrifoglio, F., Damante, G., Bhakat, K. K., et al. (2008) · Free Radical Research · doi:10.1080/10715760701765616 · Cited by 58
“proapoptotic functions through p53-mediated activation [8,40,41] of p21, leading to cell cycle arrest by inhibiting cyclin-dependent kinase [44] and cyclin G [45].”
Background
Differential regulation of transcription and induction of programmed cell death by human p53‐family members p63 and p73
Dietz, S., Rother, K., Bamberger, C., Schmale, H., Mössner, J., & Engeland, K. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03093-4 · Cited by 59
Cytokine-Stimulated T Lymphocyte Proliferation Is Regulated by p27Kip1 1
Zhang, S., Lawless, V. A., & Kaplan, M. H. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.11.6270 · Cited by 60
CHOP-dependent Regulation of p21/waf1 During ER Stress
Mihailidou, C., Papazian, I., Papavassiliou, A. G., & Kiaris, H. (2010) · Cellular Physiology and Biochemistry · doi:10.1159/000315096 · Cited by 59
High Dub3 Expression in Mouse ESCs Couples the G1/S Checkpoint to Pluripotency
van der Laan, S., Tsanov, N., Crozet, C., & Maiorano, D. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.10.003 · Cited by 59
5-Fluorouracil (5-FU) induced apoptosis in gastric cancer cell lines: role of the p53 gene
Osaki, M., Tatebe, S., Goto, A., Hayashi, H., Oshimura, M., & Ito, H. (1997) · APOPTOSIS · doi:10.1023/a:1026476801463 · Cited by 59
“mouse cells without p21/waf1 genes have been shown to undergo apoptosis following γ-irradiation, implying that apoptosis does not require the p21/waf1 gene.(28)”
OCT4 maintains self-renewal and reverses senescence in human hair follicle mesenchymal stem cells through the downregulation of p21 by DNA methyltransferases
Lü, Y., Qu, H., Qi, D., Xu, W., Liu, S., Jin, X., Song, P., Guo, Y., Jia, Y., Wang, X., et al. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-1120-x · Cited by 58
“p21 coordinates cellular senescence by inducing cell cycle arrest [41].”
Melatonin reduces X-ray irradiation-induced oxidative damages in cultured human skin fibroblasts
Kim, B. C., Shon, B. S., Ryoo, Y. W., Kim, S. P., & Lee, K. (2001) · Journal of Dermatological Science · doi:10.1016/s0923-1811(01)00088-3 · Cited by 59
“These results are in concordance with previous studies [21,22] that irradiation of normal human skin fibroblast cultures resulted in activation of p53 via post-translational stabilization, and this led to increased expression of p21 gene, which encodes an inhibitor of cyclin-dependent kinases that are required for G1/…”
Result
P21(Cip1/WAF1) expression in the mouse testis before and after X irradiation
Beumer, T. L., Roepers‐Gajadien, H. L., Gademan, I. S., Rutgers, D. H., & de Rooij, D. G. (1997) · Molecular Reproduction and Development · doi:10.1002/(sici)1098-2795(199707)47:3 · Cited by 59
Regenerative Response in Ischemic Brain Restricted by p21cip1/waf1
Qiu, J., Takagi, Y., Harada, J., Rodrigues, N. P., Moskowitz, M. A., Scadden, D. T., & Cheng, T. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031385 · Cited by 59
“We obtained heterozygous 129/SV p21 / mice (15) from the laboratory of Tyler Jacks (Massachusetts Institute of Technology, Cambridge, MA) and homozygous 129/SV p53 / or 129/SV p53 / mice from Jackson Laboratory under the permission of the Subcommittee on Research Animal Care of the Massachusetts General Hospital.”
Method
Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase
Vaziri, H., & Benchimol, S. (1999) · Oncogene · doi:10.1038/sj.onc.1203016 · Cited by 59
“In the absence of p53, pRb or p21WAF1, the cell cycle arrest pathway induced by DNA damage is lost (Kastan et al., 1992; Brugarolas et al., 1995; Deng et al., 1995; Harrington et al., 1998).”
Background
The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage
Salomoni, P., Bernardi, R., Bergmann, S., Changou, A., Tuttle, S. L., & Pandolfi, P. P. (2004) · Blood · doi:10.1182/blood-2004-09-3782 · Cited by 59
A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest
Tsabar, M., Mock, C. S., Venkatachalam, V., Reyes, J. S., Karhohs, K. W., Oliver, T. G., Regev, A., Jambhekar, A., & Lahav, G. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107995 · Cited by 54
“The p53 target gene critical for mediating cell cycle arrest is CDKN1A, which encodes the cyclin-dependent kinase inhibitor p21 (Brugarolas et al., 1995; el-Deiry et al., 1993; Harper et al., 1993).”
p21CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses
Fernández-Arias, C., Ballesteros‐Tato, A., García, M. I., Martín‐Caballero, J., Flores, J. M., Martínez‐A, C., & Balomenos, D. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2296 · Cited by 59
“Although p21 deletion was predicted to lead to tumor development, it did not lead to spontaneous cancer in young mice (2, 3).”
Background
Cell Cycle Arrest and Cell Death Are Controlled by p53-dependent and p53-independent Mechanisms in Tsg101-deficient Cells
Carstens, M. J., Krempler, A., Triplett, A. A., van Lohuizen, M., & Wagner, K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400408200 · Cited by 58
Paradigms of Growth Control: Relation to Cdk Activation
Olashaw, N., & Pledger, W. J. (2002) · Science Signaling · doi:10.1126/stke.2002.134.re7 · Cited by 59
Selective Inactivation of p53 Facilitates Mouse Epithelial Tumor Progression without Chromosomal Instability
Lu, X., Magrane, G., Yin, C., Louis, D. N., Gray, J. W., & Dyke, T. V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.17.6017-6030.2001 · Cited by 55
“For example, p53 regulates a G1 checkpoint in fibroblasts in response to DNA damage, a response that requires transcriptional activation of the p53 target gene p21 (7, 14).”
Background
p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions
Fujita, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236023 · Cited by 59
“Mouse embryonic fibroblasts lacking p21Waf1/Cip1 fail to undergo p53-dependent G1 arrest after DNA damage [55].”
BackgroundInfluential
Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 58
CDK inhibitor p21 is prosurvival in adriamycin-induced podocyte injury, in vitro and in vivo
Marshall, C. B., Krofft, R. D., Pippin, J. W., & Shankland, S. J. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00216.2009 · Cited by 57
“BALB/c mice, a strain carrying the recessive ADR susceptibility gene (67, 68), were backcrossed against c57B6 p21 / mice (4) to yield a 12th generation BALB/c p21 / strain.”
Method
Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor
Nag, D., Bhanja, P., Riha, R., Sánchez-Guerrero, G., Kimler, B. F., Tsue, T. T., Lominska, C. E., & Saha, S. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2751 · Cited by 59
Molecular control of cell density-mediated exit to quiescence
Fan, Y., & Meyer, T. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109436 · Cited by 54
“Nevertheless, unlike p21, whose deletion has only small effects on mouse development (Brugarolas et al., 1995; Deng et al., 1995), p27 deletion in mice results in increased cell proliferation, multiorgan hyperplasia, and larger body size (Fero et al., 1996; Kiyokawa et al., 1996; Nakayama et al.,…”
Background
Mdm2: A Regulator of Cell Growth and Death
Alarcon-Vargas, D., Takahashi, S., & Ronai, Z. A. (2003) · Advances in cancer research · doi:10.1016/s0065-230x(03)01001-7 · Cited by 57
p21CIP1 Is Dispensable for the G2 Arrest Caused by Genistein in Human Melanoma Cells
Casagrande, F., & Darbon, J.-M. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4914 · Cited by 57
Intact Follicular Maturation and Defective Luteal Function in Mice Deficient for Cyclin- Dependent Kinase-4
Moons, D. S., Jirawatnotai, S., Tsutsui, T., Franks, R. R., Parlow, A. F., Hales, D. B., Gibori, G., Fazleabas, A. T., & Kiyokawa, H. (2002) · Endocrinology · doi:10.1210/endo.143.2.8611 · Cited by 57
“lishing G1 arrest in response to DNA damage (10, 11).”
Background
Human RAD9 checkpoint control/proapoptotic protein can activate transcription of p21
Yin, Y., Zhu, A., Jin, Y. J., Liu, Y., Zhang, X., Hopkins, K. M., & Lieberman, H. B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403130101 · Cited by 56
Critical Function for SIP, a Ubiquitin E3 Ligase Component of the β-Catenin Degradation Pathway, for Thymocyte Development and G1 Checkpoint
Fukushima, T., Zapata, J. M., Singha, N. C., Thomas, M., Kress, C. L., Krajewska, M., Krajewski, S., Ronai, Z. A., Reed, J. C., & Matsuzawa, S. (2006) · Immunity · doi:10.1016/j.immuni.2005.12.002 · Cited by 56
Age-Specific Functional Epigenetic Changes in p21 and p16 in Injury-Activated Satellite Cells
Li, J., Han, S., Cousin, W., & Conboy, I. M. (2014) · Stem Cells · doi:10.1002/stem.1908 · Cited by 56
Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells
Lee, L. R., Teng, P.-N., Nguyen, H., Hood, B. L., Kavandi, L., Wang, G., Turbov, J. M., Thaete, L. G., Hamilton, C. A., Maxwell, G. L., et al. (2013) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-12-0493 · Cited by 56
“The Cip/Kip family plays a critical role in the cellular response to DNA damage for cell-cycle arrest (44, 45) and is upregulated in response to antiproliferative signals for cell-cycle arrest (46, 47).”
Background
Diallyl disulfide induces reversible G2/M phase arrest on a p53-independent mechanism in human colon cancer HCT-116 cells
Jo, H. J., Song, J., Kim, K., Cho, Y. H., Kim, K., & Park, Y. (2008) · Oncology Reports · doi:10.3892/or.19.1.275 · Cited by 56
p21Cip1 nullizygosity increases tumor metastasis in irradiated mice.
Jackson, R. J., Engelman, R. W., Coppola, D., Cantor, A. B., Wharton, W., & Pledger, W. J. (2003) · PubMed · Cited by 56
p21: structure and functions associated with cyclin-CDK binding
Ball, K. L. (1997) · Springer eBooks · doi:10.1007/978-1-4615-5371-7_10 · Cited by 56
Senescence-associated extracellular vesicle release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases
Tanaka, Y., & Takahashi, A. (2020) · The Journal of Biochemistry · doi:10.1093/jb/mvaa109 · Cited by 57
RBMS2 inhibits the proliferation by stabilizing P21 mRNA in breast cancer
Sun, X., Hu, Y., Wu, J., Shi, L., Zhu, L., Xi, P.-W., Wei, J., & Ding, Q. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0968-z · Cited by 55
Cdk2-dependent Inhibition of p21 Stability via a C-terminal Cyclin-binding Motif
Zhu, H., Nie, L., & Maki, C. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m407352200 · Cited by 55
Genetic Analysis of Mammalian Cyclin-Dependent Kinases and Their Inhibitors
Malumbres, M., Ortega, S., & Barbacid, M. (2000) · Biological Chemistry · doi:10.1515/bc.2000.105 · Cited by 56
“A null allele of p21Cip1 was generated in embryonic stem (ES) cells by replacing the p21Cip1 coding sequence with a neomycin-resistance cassette (Brugarolas et al., 1995; Deng et al., 1995).”
BackgroundMethod
Functional Analysis of a p21 Mutant (Arg94→ Trp) Identified in a Human Breast Carcinoma
Balbı́n, M., Hannon, G. J., Pendás, A. M., Ferrando, A. A., Vizoso, F. J., Fueyo, A., & López-Otı́n, C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.26.15782 · Cited by 55
“In fact, and according to recent data (Deng et al., 1995; Brugarolas et al., 1995), mice lacking p21, despite being defective in G1 checkpoint control, have not developed spontaneous malignancies during the first 7 months of observation, suggesting that p53-dependent suppression of early tumor…”
BackgroundSelf-citation
Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells
Fotedar, R., Brickner, H., Saadatmandi, N., Rousselle, T., Diederich, L., Munshi, A., Jung, B. H., Reed, J. C., & Fotedar, A. (1999) · Oncogene · doi:10.1038/sj.onc.1202693 · Cited by 55
“Our result that p21 expression leads to hypersensitivity to radiation induced death is in contrast to previous work showing that radiation induced p53 dependent apoptosis is una ected in p21 null mice (Brugarolas et al., 1995; Deng et al., 1995).”
BackgroundResultInfluential
Ras versus cyclin-dependent kinase inhibitors
Lloyd, A. C. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80060-9 · Cited by 55
Growth inhibitory effect of interferon-beta is associated with the induction of cyclin-dependent kinase inhibitor p27Kip1 in a human gastric carcinoma cell line.
Kuniyasu, H., Yasui, W., Kitahara, K., Naka, K., Yokozaki, H., Akama, Y., Hamamoto, T., Tahara, H., & Tahara, E. (1997) · PubMed · Cited by 55
The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death
Chari, N. S., Pinaire, N. L., Thorpe, L., Medeiros, L. J., Routbort, M. J., & McDonnell, T. J. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0327-9 · Cited by 54
“Importantly, it has been demonstrated that miR-34 can induce G1 cell cycle arrest in the absence of p21 providing a potential molecular basis for p53-dependent G1 arrest in p21-null MEFs [91, 109].”
Background
Wild-Type TP53 Inhibits G2-Phase Checkpoint Abrogation and Radiosensitization Induced by PD0166285, a WEE1 Kinase Inhibitor
Li, J., Wang, Y., Sun, Y., & Lawrence, T. S. (2002) · Radiation Research · doi:10.1667/0033-7587(2002)157[0322:wttigp]2.0.co;2 · Cited by 54
MECHANISMS OF CELL-CYCLE CHECKPOINTS: AT THE CROSSROADS OF CARCINOGENESIS AND DRUG DISCOVERY*
Flatt, P. M., & Pietenpol, J. A. (2000) · Drug Metabolism Reviews · doi:10.1081/dmr-100102335 · Cited by 54
pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120 E4F
Lluis Fajas, A., Paul, C., Zugasti, O., Cam, L. L., Polanowska, J., Fabbrizio, E., Medema, R. H., Vignais, M., & Sardet, C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130198397 · Cited by 54
Nucleotide excision repair gene (ERCC1) deficiency causes G 2 arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21
Núñez, F., Chipchase, M. D., Clarke, A. R., & Melton, D. W. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.9.1073 · Cited by 56
“cannot arrest in G1 after DNA damage (17, 18), and human p21-deficient cells show similar characteristics”
Background
Cyclin A Is a Mediator of p120 E4F -Dependent Cell Cycle Arrest in G 1
Lluis Fajas, A., Paul, C., Vié, A., Estrach, S., Medema, R. H., Blanchard, J. M., Sardet, C., & Vignais, M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.8.2956-2966.2001 · Cited by 54
“p212/2 mouse embryonic fibroblasts (MEFs) (gift from T. Jacks) ( 3 ), p532/2 MEFs (gift from L. Donehower) (8), pRB2/2 MEFs (gift from D. Cobrinik), WT MEFs, NIH 3T3 cells, CCL39”
Expression of the Cell Cycle Phosphatase cdc25C Is Down-Regulated by the Tumor Suppressor Protein p53 but Not by p73
Krause, K., Haugwitz, U., Wasner, M., Wiedmann, M. W., Mössner, J., & Engeland, K. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5040 · Cited by 53
A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo
Delebinski, C. I., Twardziok, M., Kleinsimon, S., Hoff, F., Mulsow, K., Rolff, J., Jäger, S., Eggert, A., & Seifert, G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0133892 · Cited by 53
“P21 and p27 are cyclin-dependent kinase inhibitors both of which function as regulators of cell cycle progression in a p53-dependent or independent way [78]; [79, 80].”
Background
Deficient DNA Damage Response and Cell Cycle Checkpoints Lead to Accumulation of Point Mutations in Human Embryonic Stem Cells
Hyka‐Nouspikel, N., Desmarais, J. A., Gokhale, P. J., Jones, M., Meuth, M., Andrews, P. W., & Nouspikel, T. P. (2012) · Stem Cells · doi:10.1002/stem.1177 · Cited by 52
Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer
Ghosh (2010) · International Journal of Oncology · doi:10.3892/ijo_00000627 · Cited by 52
Antibiotic drug tigecycline inhibits melanoma progression and metastasis in a p21CIP1/Waf1-dependent manner
Hu, H., Dong, Z., Tan, P., Zhang, Y., Liu, L., Yang, L., Liu, Y., & Cui, H. (2015) · Oncotarget · doi:10.18632/oncotarget.6419 · Cited by 52
“To affirm the results, we measured the expression of CDK2 and Cyclin E which could promote cells to go through the G1/S checkpoint by Western blot.”
BackgroundResultInfluential
Cellular senescence in the tumor microenvironment and context‐specific cancer treatment strategies
Yasuda, T., Baba, H., & Ishimoto, T. (2021) · FEBS Journal · doi:10.1111/febs.16231 · Cited by 53
CDC2 is down-regulated by ionizing radiation in a p53-dependent manner.
Azzam, E. I., Toledo, S. D., Pykett, M. J., Nagasawa, H. T., & Little, J. B. (1997) · PubMed · Cited by 53
UV Radiation Is a Transcriptional Inducer of p21Cip1/Waf1Cyclin-Kinase Inhibitor in a p53-Independent Manner
Haapajärvi, T., Kivinen, L., Heiskanen, A., Bordes, C. D., Datto, M., Wang, X.-F., & Laiho, M. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4403 · Cited by 53
The unbalanced p53/SIRT1 axis may impact lymphocyte homeostasis in COVID-19 patients
Bordoni, V., Tartaglia, E., Sacchi, A., Fimia, G. M., Cimini, E., Casetti, R., Notari, S., Grassi, G., Marchioni, L., Bibas, M., et al. (2021) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2021.02.019 · Cited by 54
“Furthermore, a significant higher level of p21, an essential mediator of p53-dependent cell-cycle arrest (Brugarolas et al., 1995), was observed in COVID-19 patients than in HD (Figure 1D).”
Triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53
Sun, Y., Xiao, L., Wang, D., Ji, Y., Yang, Y., Ma, R., & Chen, X. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.3850 · Cited by 52
Lipid peroxide‐induced redox imbalance differentially mediates CaCo‐2 cell proliferation and growth arrest
Gotoh, Y., Noda, T., Iwakiri, R., Fujimoto, K., Rhoads, C. A., & Aw, T. Y. (2002) · Cell Proliferation · doi:10.1046/j.1365-2184.2002.00241.x · Cited by 52
G1 versus G2 cell cycle arrest after adriamycin‐induced damage in mouse Swiss3T3 cells
Siu, W. Y., Yam, C. H., & Poon, R. Y. C. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01481-7 · Cited by 52
The Cyclin-dependent Kinase Inhibitor p21 Mediates the Growth Inhibitory Effect of Phorbol Esters in Human Venous Endothelial Cells
Zezula, J., Sexl, V., Hutter, C., Karel, A., Schütz, W., & Freissmuth, M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.47.29967 · Cited by 52
p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations
Viale, G., Pellegrini, C., Mazzarol, G., Maisonneuve, P., Silverman, M. L., & Bòsari, S. (1999) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199902)187:3 · Cited by 52
Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis
Hartmann, B. L., Geley, S., Loeffler, M. W., Hattmannstorfer, R., Strasser-Wozak, E. M., Auer, B., & Kofler, R. (1999) · Oncogene · doi:10.1038/sj.onc.1202339 · Cited by 52
“G1 growth arrest has been shown to be unrelated to, or even protect from, apoptosis in most systems of p53-mediated apoptosis (Brugarolas et al., 1995; Deng et al., 1995; Gorospe et al., 1997).”
Background
Differential Activation of p53 Targets in Cells Treated with Ultraviolet Radiation That Undergo Both Apoptosis and Growth Arrest
Reinke, V., & Lozano, G. (1997) · Radiation Research · doi:10.2307/3579567 · Cited by 52
On the TRAIL from p53 to apoptosis?
Kastan, M. B. (1997) · Nature Genetics · doi:10.1038/ng1097-130 · Cited by 52
Recent advances on cyclins, CDKs and CDK inhibitors
Martı́n-Castellanos, C., & Moreno, S. (1997) · Trends in Cell Biology · doi:10.1016/s0962-8924(96)10055-6 · Cited by 52
Biguanides drugs: Past success stories and promising future for drug discovery
Grytsai, O., Myrgorodska, I., Rocchi, S., Ronco, C., & Benhida, R. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113726 · Cited by 51
Nutrition for Healthy Skin
Krutmann, J., & Humbert, P. G. (2010) · Springer eBooks · doi:10.1007/978-3-642-12264-4 · Cited by 82
Association between TP53 and p21 genetic polymorphisms and acute side effects of radiotherapy in breast cancer patients
Tan, X., Popanda, O., Ambrosone, C. B., Kropp, S., Helmbold, I., von Fournier, D., Haase, W., Sautter-Bihl, M. L., Wenz, F. K., Schmezer, P., et al. (2005) · Breast Cancer Research and Treatment · doi:10.1007/s10549-005-9119-2 · Cited by 51
“p21, together with p53, is directly involved in G1/S checkpoint control in response to IR [5].”
Background
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
Apoptosis and the cell cycle: the p53 connection
Choisy, C., & Yonish-Rouach, E. (1998) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400339 · Cited by 51
“Mice lacking p21 were shown to be defective in the G1 checkpoint control (Brugarolas et al, 1995; Deng et al, 1995).”
Background
ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint
Garner, A. P., Weston, C. R., Todd, D. E., Balmanno, K., & Cook, S. J. (2002) · Oncogene · doi:10.1038/sj.onc.1206000 · Cited by 50
“…et al., 1995; Deng et al., 1995; Waldmann et al., 1995) is critical for both imposing and maintaining the DNA damage-induced G1 checkpoint (Brugarolas et al., 1995; Deng et al., 1995). p21CIP1 over-expression results in inhibition of cyclin-dependent kinase 2 (CDK2)-containing complexes…”
Background
Mdm-2: “big brother” of p53
Momand, J. A., & Zambetti, G. P. (1997) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19970301)64:3 · Cited by 167
Features of Macrophage Differentiation Induced by p19INK4d, a Specific Inhibitor of Cyclin D–Dependent Kinases
Adachi, M., Roussel, M. F., Havenith, K., & Sherr, C. J. (1997) · Blood · doi:10.1182/blood.v90.1.126 · Cited by 51
p53-Oriented cancer therapies: Current progress
Gallagher, W. M., & Brown, R. E. (1999) · Annals of Oncology · doi:10.1023/a:1008368500557 · Cited by 51
Radiation Induction of p53 in Cells from Nijmegen Breakage Syndrome Is Defective but Not Similar to Ataxia-Telangiectasia
Matsuura, K., Balmukhanov, T. S., Tauchi, H., Weemaes, C. M. R., Smeets, D. F. C. M., Chrzańowska, K., Endou, S., Matsuura, S., & Komatsu, K. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7924 · Cited by 51

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)
ORCID: Brugarolas, James
Gordon, Jeffrey I.
Jacks, Tyler
Hannon, Gregory J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1995-10
Volume: 377
Issue: 6549
Pages: 552-557
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/377552a0
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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

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

Radiation-induced cell cycle arrest compromised by p21 deficiency

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks