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

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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

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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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Background
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Background
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Background
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Background
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Background
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Microgravity Inhibits Resting T Cell Immunity in an Exposure Time-Dependent Manner
Luo, H., Wang, C., Feng, M., & Zhao, Y. X. (2014) · International Journal of Medical Sciences · doi:10.7150/ijms.7651 · Cited by 43
Therapeutic Response to Non-genotoxic Activation of p53 by Nutlin3a Is Driven by PUMA-Mediated Apoptosis in Lymphoma Cells
Valente, L. J., Aubrey, B. J., Herold, M. J., Kelly, G. L., Happo, L., Scott, C. L., Newbold, A., Johnstone, R. W., Huang, D. C. S., Vassilev, L. T., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.059 · Cited by 40
“The cyclin-dependent kinase inhibitor (CDKI) p21 is critical for p53-mediated G1/S cell-cycle arrest and senescence (Brugarolas et al., 1995; Chang et al., 1999; Deng et al., 1995), whereas the BH3-only proteins PUMA and (to a lesser extent) NOXA are required for the induction of apoptosis (Jeffers et al.”
Background
Δ40p53α suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells
Ota, A., Nakao, H., Sawada, Y., Karnan, S., Wahiduzzaman, M., Inoue, T., Kobayashi, Y., Yamamoto, T., Ishii, N., Ohashi, T., et al. (2017) · Journal of Cell Science · doi:10.1242/jcs.190736 · Cited by 41
“p21, a well-known p53 target gene, is upregulated during replicative senescence and functions as an inhibitor of proliferation (Lanigan et al., 2011; Brugarolas et al., 1995).”
Background
Human Colorectal Cancer from the Perspective of Mouse Models
Šťastná, M., Janečková, L., Hrčkulák, D., Kříž, V., & Kořínek, V. (2019) · Genes · doi:10.3390/genes10100788 · Cited by 43
The relationship between cisplatin - induced apoptosis and p53 , bcl - 2 and bax expression in human lung cancer cells
Han, J. Y., Chung, Y. J., Kim, J. S., Rhyu, M. G., Kim, H. K., Lee, K. S., & Park, S. W. (1999) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.1999.14.1.42 · Cited by 41
CDIP, a novel pro‐apoptotic gene, regulates TNFα‐mediated apoptosis in a p53‐dependent manner
Brown, L. M., Ongusaha, P. P., Kim, H.-G., Nuti, S. L., Mandinova, A., Lee, J. W., Khosravi‐Far, R., Aaronson, S. A., & Lee, S. W. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601779 · Cited by 41
“…p53 activates G1 arrest is well characterized and involves primarily the transcrip- tional activation of the cyclin-dependent kinase inhibitor p21Waf1 (el-Deiry et al, 1993; Brugarolas et al, 1995; Deng et al, 1995), apoptosis induced by p53 is proving to be a much more complex cellular process.”
Background
Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors
Matheu, A., Klatt, P., & Serrano, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508270200 · Cited by 41
Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis
Allemand, I., Anglo, A., Jeantet, A. Y., Cerutti, I., & May, E. (1999) · Oncogene · doi:10.1038/sj.onc.1203052 · Cited by 41
“The involvement of one of its target genes, the cyclin-dependent kinase inhibitor p21waf, in G1 arrest has been demonstrated in vivo (Brugarolas et al., 1995; Deng et al., 1995).”
Background
MicroRNAs are significantly influenced by p53 and radiation in HCT116 human colon carcinoma cells
An (2009) · International Journal of Oncology · doi:10.3892/ijo_00000295 · Cited by 40
The role of cullin4B in human cancers
Li, Y., & Wang, X. (2017) · Experimental Hematology and Oncology · doi:10.1186/s40164-017-0077-2 · Cited by 40
“Many studies have manifested that p21 accumulates during G1 phase but degraded during S phase [43].”
Background
RETRACTED ARTICLE: REST regulates the cell cycle for cardiac development and regeneration
Zhang, D., Wang, Y., Lu, P., Wang, P., Yuan, X., Yan, J., Cai, C., Chang, C., Zheng, D., Wu, B., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02210-y · Cited by 41
Retracted
Involvement of long non-coding RNA HULC (highly up-regulated in liver cancer) in pathogenesis and implications for therapeutic intervention
Klec, C., Gutschner, T., Panzitt, K., & Pichler, M. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1570499 · Cited by 40
Genetic cooperation between p21Cip1 and INK4 inhibitors in cellular senescence and tumor suppression
Quereda, V., Martinalbo, J., Dubus, P. R., Carnero, A., & Malumbres, M. (2007) · Oncogene · doi:10.1038/sj.onc.1210578 · Cited by 41
“Deletion of p21 results in altered response to DNA damage responses and increased tumor susceptibility, specifically in mesenchymal and hematopoietic cells, at an advanced age (Brugarolas et al., 1995; Martin-Caballero et al., 2001).”
BackgroundInfluential
Human GTSE-1 Regulates p21CIP1/WAF1 Stability Conferring Resistance to Paclitaxel Treatment
Bublik, D. R., Scolz, M., Triolo, G., Monte, M., & Schneider, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.045948 · Cited by 40
Stabilization of p53 and transactivation of its target genes in response to replication blockade
Nayak, B. K., & Das, G. M. (2002) · Oncogene · doi:10.1038/sj.onc.1205889 · Cited by 40
“The role of p53 in G1 and G2 checkpoints in response to genotoxic stress has been well documented (Brugarolas et al., 1995; Bunz et al., 1998; Chan et al., 2000; Hermeking et al., 1997; Wang et al., 1999).”
Background
MyoD induces apoptosis in the absence of RB function through a p21WAF1-dependent re-localization of cyclin/cdk complexes to the nucleus
Peschiaroli, A., Figliola, R., Coltella, L., Strom, A., Valentini, A., D’Agnano, I., & Maione, R. (2002) · Oncogene · doi:10.1038/sj.onc.1206010 · Cited by 40
“RB7/7 MEFs, derived from RB knock-out mice (Jacks et al., 1992), and p217/7 MEFs, derived from p21 knock-out mice (Brugarolas et al., 1995), were kindly provided by Dr M Caruso (Istituto Biologia Cellulare CNR, Roma, Italy) and Dr M Crescenzi (Istituto Superiore di Sanità, Roma, Italy),…”
Method
Why are there so many CDK inhibitors?
Xiong, Y. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(96)00012-1 · Cited by 40
p53 Mediates Apoptotic Crisis in Primary Abelson Virus-Transformed Pre-B Cells
Unnikrishnan, I., Radfar, A., Jenab-Wolcott, J., & Rosenberg, N. E. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.4825 · Cited by 40
“Activation of p53 can induce G1 arrest by inducing the p21 Cip-1 cyclin-dependent kinase inhibitor and other target molecules (5, 8, 10, 11, 16, 55).”
Multifaceted effect of chlorpromazine in cancer: implications for cancer treatment
Kamgar-Dayhoff, P., & Brelidze, T. I. (2021) · Oncotarget · doi:10.18632/oncotarget.28010 · Cited by 43
Ikaros‐1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons
Martín‐Ibáñez, R., Crespo, E., Urbán, N., Sergent‐Tanguy, S., Herranz, C., Jaumot, M., Valiente, M., Long, J. E., Pineda, J. R., Andreu, C., et al. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22215 · Cited by 39
“…Charles River Laboratories, Les Oncins, France); Dlx-5/6-Cre-IRES-GFP transgenic mice (Stenman et al., 2003); and Ikaros (Wang et al., 1996), Dlx-1/2 (Qiu et al., 1997), Ebf-1 (Lin and Grosschedl, 1995), and p21 (Brugarolas et al., 1995) knockout mice (–/–) were used (see Table 1 for details).”
Method
Discrete signaling pathways participate in RB-dependent responses to chemotherapeutic agents
Mayhew, C. N., Perkin, L. M., Zhang, X., Sage, J., Jacks, T., & Knudsen, E. S. (2004) · Oncogene · doi:10.1038/sj.onc.1207503 · Cited by 39
“Cell cycle checkpoints elicited by a number of clinically relevant agents signal for growth arrest through RB via the key upstream checkpoint genes p53 (Kastan et al., 1992; Slebos et al., 1994; Smith et al., 1994) and p21cip1 (Brugarolas et al., 1995; Deng et al., 1995).”
BackgroundSelf-citation
Transmission distortion by loss of p21 or p27 cyclin-dependent kinase inhibitors following competitive spermatogonial transplantation
Kanatsu‐Shinohara, M., Takashima, S., & Shinohara, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914448107 · Cited by 38
“Although KO mice have been produced for Cip/Kip family genes, no apparent SSC phenotype has been reported, and the effects of these genes remain unclear (7, 8).”
Background
Differential response between the p53 ubiquitin–protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells
Duan, W., Gao, L., Wu, X., Zhang, Y., Otterson, G. A., & Villalona-Calero, M. A. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.07.005 · Cited by 38
Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice
Talmasov, D., Zhang, X., Yu, B., Nandan, M. O., Bialkowska, A. B., Elkarim, E. A., Kuruvilla, J., Yang, V. W., & Ghaleb, A. M. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00080.2014 · Cited by 37
Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment
Kim, B. C., Lee, H. C., Lee, J., Choi, C., Kim, D.-K., Lee, J. C., Ko, Y., & Lee, J. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.286 · Cited by 41
“Cells were harvested 2 days after transfection, and then isolated RNA was subjected to qRT–PCR using RL-and FL-speciﬁc suggesting that p21 expression and activity must be tightly regulated by multiple mechanisms (Brugarolas et al , 1995; Deng et al , 1995).”
Molecular evidence of anti-leukemia activity of gypenosides on human myeloid leukemia HL-60 cells in vitro and in vivo using a HL-60 cells murine xenograft model
Lin, J., Hsu, H.-Y., Yang, J., Lu, K.-W., Wu, R. S.-C., Wu, K., Lai, T.-Y., Chen, P., Ma, C.-Y., Wood, W. G., et al. (2011) · Phytomedicine · doi:10.1016/j.phymed.2011.03.009 · Cited by 38
G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv
Doumont, G., Martoriati, A., Beekman, C., Bogaerts, S., Mee, P. J., Bureau, F., Colombo, E., Alcalay, M., Bellefroid, E., Marchesi, F., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600769 · Cited by 40
“A role of p21 in the p53-dependent G1 checkpoint had already been clearly established (Brugarolas et al, 1995; Deng et al, 1995).”
Background
P16INK4A is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation
Chazal, M., Marionnet, C., Michel, L., Mollier, K., Dazard, J.-E., Della-Valle, V., Larsen, C., Gras, M.-P., & Basset‐Séguin, N. (2002) · Oncogene · doi:10.1038/sj.onc.1205349 · Cited by 39
“In this study, we compared the expression of P16INK4A, P53 and P53-controlled protein (such as P21waf1/cip1, MDM2 and Bax) expression during UVB radiation of human keratinocytes.”
BackgroundInfluential
Expression of apoptosis-related proteins in endometriomas and benign and malignant ovarian tumours
Fauvet, R., Poncelet, C., Hugol, D., Lavaur, A., Feldmann, G., & Daraï, É. (2003) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-003-0813-3 · Cited by 38
“Indeed, the p53-inducible gene p21 encodes an inhibitor of cyclin-dependent kinases involved in G1 arrest [2, 5, 10].”
Background
Intestinal cell cycle regulation
Ko, T. C., Bresnahan, W. A., & Thompson, E. A. (1997) · Springer eBooks · doi:10.1007/978-1-4615-5371-7_4 · Cited by 38
p53 activates G1 checkpoint following DNA damage by doxorubicin during transient mitotic arrest
Hyun, S., & Jang, Y. (2014) · Oncotarget · doi:10.18632/oncotarget.3103 · Cited by 38
“So far, p53 was observed to be involved in the G1 phase checkpoint, which protects against an abnormal genome and induces cell cycle arrest before the S phase in response to DNA damage [39-42].”
Background
TBX3, the gene mutated in ulnar-mammary syndrome, promotes growth of mammary epithelial cells via repression of p19ARF, independently of p53
Platonova, N., Scotti, M., Babich, P. S., Bertoli, G. R., Mento, E., Meneghini, V., Egeo, A., Zucchi, I., & Merlo, G. R. (2007) · Cell and Tissue Research · doi:10.1007/s00441-006-0364-4 · Cited by 38
“Decreased expression of p21 CIP1/WAF ( − 30±2”
Influential
Developmental Arrest of T Cells in Rpl22-Deficient Mice Is Dependent upon Multiple p53 Effectors
Stadanlick, J. E., Zhang, Z., Lee, S.-Y., Hemann, M., Biery, M. C., Carleton, M. O., Zambetti, G. P., Anderson, S. J., Oravecz, T., & Wiest, D. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100029 · Cited by 36
“Among these factors, the most frequently implicated in regulating cell growth and survival are p21waf and PUMA, respectively (21, 24, 41).”
Background
The tumor suppressor geneTrp53protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens
Wiley, L. A., Rajagopal, R., Dattilo, L. K., & Beebe, D. C. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.006593 · Cited by 37
“Germline deletion of Cdkn1a, the gene encoding p21CIP1/WAF1, did not impair normal development or cell cycle withdrawal during terminal differentiation (Brugarolas et al., 1995; Deng et al., 1995).”
Background
Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53
Valente, L. J., Grabow, S., Vandenberg, C. J., Strasser, A., & Janic, A. (2015) · Oncogene · doi:10.1038/onc.2015.457 · Cited by 37
MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL
Nam, R. K., Benatar, T., Wallis, C. J. D., Kobylecky, E., Amemiya, Y., Sherman, C., & Seth, A. K. (2019) · The Prostate · doi:10.1002/pros.23871 · Cited by 37
“AKT activation leads to cyclin D1 upregulation through inhibition of GSK3β.”
Influential
Depletion of the histone chaperone tNASP inhibits proliferation and induces apoptosis in prostate cancer PC-3 cells
Alekseev, O., Richardson, R. T., Tsuruta, J. K., & O’Rand, M. G. (2011) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-9-50 · Cited by 37
“Although it is well established that p21 mediates p53-dependant G1/ S phase growth arrest in response to DNA damage [46,47], p21 expression could be induced by mechanisms independent of p53.”
Background
Differences in activation of G2/M checkpoint in keratinocytes after genotoxic stress induced by hydrogen peroxide and ultraviolet a radiation
Thorn, T., Gniadecki, R., Petersen, A., Vičanová, J., & Wulf, H. C. (2001) · Free Radical Research · doi:10.1080/10715760100300921 · Cited by 37
“The G1 checkpoint is mostly regulated by p53 which is induced directly by DNA damage and activates the cell cycle inhibitor p21Cipl/WAF[13-15]”
Background
p53: functions, mutations and sarcomas
Hung, J. Y., & Anderson, R. L. (1997) · Acta Orthopaedica Scandinavica · doi:10.1080/17453674.1997.11744705 · Cited by 37

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

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Radiation-induced cell cycle arrest compromised by p21 deficiency

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