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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“This is because this geminin reporter only accumulates during the S/G2/M parts of the cell cycle [44, 45] and p21 is degraded in the G1/S transition [33, 43].”
Background
An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis
Li, Z.-Y., Zhang, Q., Mao, J.-H., Weise, A., Mrasek, K., Fan, X., Zhang, X., Liehr, T., Lu, K. H., Balmain, A., et al. (2010) · Oncogene · doi:10.1038/onc.2010.19 · Cited by 20
“In eukaryotic DNA damage signaling pathways, tumor suppressor p53 and its transcriptional target CDKN1A (p21) have an essential role in monitoring cell-cycle checkpoints (Brugarolas et al., 1995; Deng et al., 1995; Bunz et al., 1998).”
Background
Transgenic zebrafish for modeling hepatocellular carcinoma
Nakayama, J., & Gong, Z. (2020) · MedComm · doi:10.1002/mco2.29 · Cited by 19
The Levels of H11/HspB8 DNA Methylation in Human Melanoma Tissues and Xenografts Are a Critical Molecular Marker for 5-Aza-2′-Deoxycytidine Therapy
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“Of note, our and previous findings for H11/HspB8 mimic those described for canonical tumor suppressor genes[49–54].”
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p21Cip1 Confers resistance to imatinib in human chronic myeloid leukemia cells
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Background
Attenuation of G1 checkpoint function by the non-genotoxic carcinogen phenobarbital
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S-phase-coupled apoptosis in tumor suppression
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“Consequently, deletion of p21 from colon cancer cells or mouse embryonic fibroblasts allows p53 to induce apoptosis [99–102].”
Background
Lung specific expression of a human mutant p53 affects cell proliferation in transgenic mice
Duan, W., Gao, L., Jin, D., Otterson, G. A., & Villalona-Calero, M. A. (2007) · Transgenic Research · doi:10.1007/s11248-007-9154-3 · Cited by 18
“DNA damage induced G1 arrest is primarily dependent on the ability of p53 to transactivate the cell cycle inhibitor p21WAF1/CIP1 (Martin-Caballero et al. 2001; Brugarolas et al. 1995).”
Background
Mutations in Lyar and p53 are synergistically lethal in female mice
Wang, G., Fulkerson, C. M., Malek, R. A., Ghassemifar, S., Snyder, P. W., & Mendrysa, S. M. (2012) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.23048 · Cited by 18
Chromatin modification and disease
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“(also known as WAF1 and CIP1), which exerts a G1 cell cycle arrest in response to a variety of stimuli.”
Background
Lysines in the tetramerization domain of p53 selectively modulate G1 arrest
Beckerman, R., Yoh, K. E., Mattia-Sansobrino, M., Zupnick, A., Laptenko, O., Karni-Schmidt, O., Ahn, J., Byeon, I. L., Keezer, S. M., & Prives, C. L. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1170270 · Cited by 19
Cip/Kip Cell-cycle Inhibitors: A Neuro-oncological Perspective
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Background
Evidence for the expression of radiation-induced potentially lethal damage being a p53 -dependent process
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“…arrest are triggered by different mechanisms. p21}waf-1, a downstream target of wtp53 and a dual inhibitor of cyclin-dependent kinases and proliferating cell nuclear antigen, is partly responsible for p53-mediated growth arrest (Brugarolas et al., 1995 ; Chen et al., 1996b ; Deng et al., 1995).”
Background
Expression of p53 and p21 in Primary Glioblastomas
Gross, M. W., Kraus, A., Nashwan, K., Mennel, H.-D., Engenhart‐Cabillic, R., & Schlegel, J. (2005) · Strahlentherapie und Onkologie · doi:10.1007/s00066-005-1304-z · Cited by 18
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Background
Regulation of the Cell Cycle by the Rb Tumor Suppressor Family
Ewen, M. E. (1998) · Results and problems in cell differentiation · doi:10.1007/978-3-540-69686-5_7 · Cited by 18
Deletion of p21 cannot substitute for p53 loss in rescue of mdm2 null lethality
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Self-citation
Accumulation of recombinant chromosomes and low fidelity of transmission of chromosome X DNA markers in ?-ray-induced lymphomas lacking p53
Koide, N., Matsumoto, Y., Kosugi, S., Chou, D., Sakai∞, K., Hatakeyama, K., Niwa, O., & Kominami, R. (1999) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199901)24:1 · Cited by 4
Transit-amplifying cells control R-spondins in the mouse crypt to modulate intestinal stem cell proliferation
Perez, A. C., Santos-de-Frutos, K., de la Rosa, S., Herranz-Montoya, I., Perna, C., & Djouder, N. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212405 · Cited by 17
“T; Brugarolas et al., 1995; Serrano et al., 1996), confirming that cell cycle arrest observed in ISCs from URI ( Δ / Δ )Int mice is not due to senescence.”
Role of hsa_circ_0000280 in regulating vascular smooth muscle cell function and attenuating neointimal hyperplasia via ELAVL1
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Role of Running-Activated Neural Stem Cells in the Anatomical and Functional Recovery after Traumatic Brain Injury in p21 Knock-Out Mice
Battistini, J. I., Mastrorilli, V., di Robilant, V. N., Saraulli, D., Marinelli, S., & Vecchioli, S. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032911 · Cited by 17
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Background
Tumour suppressors and cellular senescence
Chan, A. S. L., Mowla, S. N., Arora, P., & Jat, P. (2014) · IUBMB Life · doi:10.1002/iub.1335 · Cited by 20
“Mouse embryo fibroblasts null for p21 are unable to undergo a radiation-induced growth arrest (61).”
Background
Miz1 Is a Critical Repressor of cdkn1a during Skin Tumorigenesis
Hönnemann, J., Sanz‐Moreno, A., Wolf, E., Eilers, M., & Elsässer, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034885 · Cited by 17
“MizDPOZ mice were crossed on a cdkn2b [46] and cdkn1a [47] deficient background, here designated MizDPOZ;cdkn2b and MizDPOZ;cdkn1a mice, respectively.”
Background
The c-Jun and JunB transcription factors facilitate the transit of classical Hodgkin lymphoma tumour cells through G1
Zhang, J., Wu, Z., Savin, A., Yang, M., Hsu, Y.-H. R., Jantuan, E., Bacani, J. T. C., & Ingham, R. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-34199-9 · Cited by 17
Cell Cycle Effects in Radiation Oncology
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Expression and prognostic relevance of p21WAF1 in stage III esophageal squamous cell carcinoma
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HCT116 cells deficient in p21Waf1 are hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism unrelated to p21 and dependent on p53
Ferrándiz, N., Martı́n-Pérez, J., Blanco, R. E., Dönertas, D., Weber, A., Eilers, M., Dotto, G. P., Delgado, M. D., & León, J. (2009) · DNA repair · doi:10.1016/j.dnarep.2008.12.001 · Cited by 17
Transcription activity is required for p53-dependent tumor suppression
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“In this context, although p53-dependent cell-cycle G1/S arrest after DNA damage is abolished in p21 / mice, these mice are genetically stable and are not cancer prone (Brugarolas et al., 1995; Deng et al., 1995).”
Monoclonal Antibody Probes for p21 WAF1/CIP1 and the INK4 Family of Cyclin-Dependent Kinase Inhibitors
Thullberg, M., Welcker, M., Bártková, J., Kjerulff, A. A., Lukas, J., Johan, H. V. E., & Bartek, J. (2000) · Hybridoma · doi:10.1089/027245700315806 · Cited by 17

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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