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Modes of p53 regulation.
Open accessAbstract
The traditional view of p53 activation includes three steps-p53 stabilization, DNA binding, and transcriptional activation. However, recent studies indicate that each step of p53 activation is more complex than originally anticipated. Moreover, both genetic studies in mice and in vitro studies with purified components suggest that the classical model may not be sufficient to explain all aspects of p53 activation in vivo. To reconcile these differences, we propose that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p53.
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“Activation of p53 is dependent on various post translational modifications such as phosphorylation, methylation, acetylation, sumoylation, ubiquitination, and neddylation (Kruse and Gu, 2009).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kruse and Gu, 2009
In the citing paper
“This transcriptional antagonism can take place within the nucleus, as Mdm2 and Mdmx have been detected at p53-responsive promoter elements in chromatin [2].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [2]
In the citing paper
“MDM2 is a known E3 ubiquitin ligase that acts as a powerful inhibitor of the tumor suppressor P53 [141].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [141]
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Citations
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“Mechanistically, the acetylated lysines are thought to participate in mediating “antirepression” (Tang et al. 2008; Kruse and Gu 2009).”
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Self-citationDNA damage kinase signaling: checkpoint and repair at 30 years
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“This would be in keeping with p53’s ability to respond to oncogenic stress and induce the death of cells that overexpress oncogenes (Green and Kroemer, 2009; Hoffman and Liebermann, 2008; Kruse and Gu, 2009; Lowe et al., 2004).”
Smoking, p53 Mutation, and Lung Cancer
Gibbons, D. L., Byers, L. A., & Kurie, J. M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0539 · Cited by 255
“The outcome of p53 function is highly contextdependent, depending on its complex effects in activating transcriptional activity at some sites while repressing others, the balance ofwhichmay result in cell cycle arrest and repair of the damaged DNA, cellular apoptosis, senescence, metabolic changes, or autophagy (31, 3…”
BackgroundHepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis
Xu, X., Fan, Z., Kang, L., Han, J., Jiang, C., Zheng, X., Zhu, Z., Jiao, H., Lin, J., Jiang, K., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64265 · Cited by 249
“Loss of function of the p53 tumor suppressor protein has been reported to be a causative event in the pathogenesis of a large fraction of human cancers (35–37). p53 is frequently mutated in human cancers, including HCC, and many mutations of p53 lead to loss of p53 function.”
GSK-3: A Bifunctional Role in Cell Death Pathways
Jacobs, K. M., Bhave, S. R., Ferraro, D. J., Jaboin, J. J., Hallahan, D. E., & Thotala, D. K. (2012) · International Journal of Cell Biology · doi:10.1155/2012/930710 · Cited by 258
“This determines the specific cellular response, which can include survival, growth arrest, DNA repair, or apoptosis [44].”
BackgroundKumar, A., & Chandna, S. (2018) · Scientific Reports · doi:10.1038/s41598-017-18521-5 · Cited by 249
Stengel, A., Kern, W., Haferlach, T., Meggendorfer, M., Fasan, A., & Haferlach, C. (2016) · Leukemia · doi:10.1038/leu.2016.263 · Cited by 256
Surf the Post-translational Modification Network of p53 Regulation
Gu, B., & Zhu, W. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4283 · Cited by 252
Basal Dynamics of p53 Reveal Transcriptionally Attenuated Pulses in Cycling Cells
Loewer, A., Batchelor, E., Gaglia, G., & Lahav, G. (2010) · Cell · doi:10.1016/j.cell.2010.05.031 · Cited by 239
“in Cycling Cells”
BackgroundLysine methylation: beyond histones
Zhang, X., Wen, H., & Shi, X. (2011) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmr100 · Cited by 249
Jang, I., Henriques, R., Seo, H. S., Nagatani, A., & Chua, N. (2010) · The Plant Cell · doi:10.1105/tpc.109.072520 · Cited by 228
“The stimulatory effect of PIFs on phyB ubiquitination is reminiscent of the modulation of p53 ubiquitination by regulatory factors in animal cells (Sui et al., 2004; Allende-Vega et al., 2007; Kruse and Gu, 2009).”
BackgroundTargeting the nucleolus for cancer intervention
Quin, J. E., Devlin, J. R., Cameron, D. P., Hannan, K. M., Pearson, R. B., & Hannan, R. D. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.12.009 · Cited by 230
“Further, posttranslational modification and association with co-factors mediate p53 activity towards its transcriptional targets (reviewed in [129,130]).”
BackgroundControl of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53
Yoon, K. W., Byun, S., Kwon, E., Hwang, S.-Y., Chu, K., Hiraki, M., Jo, S., Weins, A., Hakroush, S., Cebulla, A., et al. (2015) · Science · doi:10.1126/science.1261669 · Cited by 230
“p53 functions as a transcription factor that is activated by various cellular stresses and governs multiple core programs in cells, including cell cycle arrest and apoptosis (17, 18).”
BackgroundWaves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells
Smolková, K., Plecitá‐Hlavatá, L., Bellancé, N., Bénard, G., Rossignol, R., & Ježek, P. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.05.003 · Cited by 232
p53-family proteins and their regulators: hubs and spokes in tumor suppression
Collavin, L., Lunardi, A., & Sal, G. D. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.35 · Cited by 225
Shi, D., & Gu, W. J. (2012) · Genes & Cancer · doi:10.1177/1947601912455199 · Cited by 220
Self-citationEpigenetic regulation of ferroptosis by H2B monoubiquitination and p53
Wang, Y., Yang, L., Zhang, X., Cui, W., Liu, Y., Sun, Q., He, Q., Zhao, S., Zhang, G., Wang, Y., et al. (2019) · EMBO Reports · doi:10.15252/embr.201847563 · Cited by 215
“It is well known that p53 plays critical roles in apoptosis, cell cycle regulation, senescence, DNA repair, and other cellular events [42].”
Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation
Lee, C. W., Ferreon, J. C., Ferreon, A. C. M., Arai, M., & Wright, P. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013078107 · Cited by 220
“Although it is clear that p53 is activated by a complex cascade of phosphorylation and other posttranslational modifications initiated by genotoxic stress, the functional roles played by individual phosphorylation sites and by multisite phosphorylation events remain poorly understood (1, 2, 4, 12).”
BackgroundPETROCELLIS, L. D., Ligresti, A., Moriello, A. S., Iappelli, M., Verde, R., Stott, C. G., Cristino, L., Orlando, P., & Marzo, V. D. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02027.x · Cited by 211
“The observed up-regulation of p53 protein expression in these cells might be either the effect or the cause of AR downregulation (Rokhlin et al., 2005; Kruse and Gu, 2009; Schiewer et al., 2012).”
BackgroundAutophagy and the Cell Cycle: A Complex Landscape
Mathiassen, S. G., Zio, D. D., & Cecconi, F. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00051 · Cited by 214
“p53 is one of the most extensively characterized tumor suppressor proteins and a central coordinator of the cellular response to acute stress (59, 60).”
BackgroundThe ubiquitin proteasome system in neuropathology
Lehman, N. L. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0560-x · Cited by 207
UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination
Liu, J., Guan, D., Dong, M., Yang, J., Wei, H., Liang, Q., Song, L., Xu, L., Bai, J., Liu, C., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0559-z · Cited by 203
Holzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00810 · Cited by 203
USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.
Fan, Y.-H., Cheng, J., Vasudevan, S. A., Dou, J., Zhang, H., Patel, R. H., Ma, I. T., Rojas, Y., Zhao, Y., Yu, Y., et al. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.400 · Cited by 199
“In unstressed cells, p53 protein level and activity are maintained at an extremely low level by its primary negative regulator, mouse double minute 2 homolog (MDM2) (human homolog HDM2).(18,19) MDM2 is an E3 ubiquitin (Ub) ligase that ubiquitinates p53, which results in proteasomal degradation of p53.”
BackgroundDysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
Lin, R.-K., Wu, C.-Y., Chang, J.-W., Juan, L., Hsu, H., Chen, C., Lu, Y.-Y., Tang, Y.-A., Yang, Y., Yang, P., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4161 · Cited by 208
Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode
Wang, D., Kon, N., Lasso, G., Jiang, L., Leng, W., Zhu, W., Qin, J., Honig, B. H., & Gu, W. J. (2016) · Nature · doi:10.1038/nature19759 · Cited by 198
Self-citationLi, W., Li, F., Zhang, X., Lin, H., & Xu, C. S. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00825-8 · Cited by 211
Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis
Yuan, L., Lv, Y., Li, H., Gao, H., Song, S., Zhang, Y., Xing, G., Kong, X., Wang, L., Li, Y., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3218 · Cited by 199
The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo
Huang, L., Yan, Z., Liao, X., Li, Y., Yang, J., Wang, Z.-G., Zuo, Y., Kawai, H., Shadfan, M., Ganapathy, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102309108 · Cited by 193
Cell signaling, post-translational protein modifications and NMR spectroscopy
Theillet, F., Smet‐Nocca, C., Liokatis, S., Thongwichian, R., Kosten, J., Yoon, M., Kriwacki, R. W., Landrieu, I., Lippens, G. M., & Selenko, P. (2012) · Journal of Biomolecular NMR · doi:10.1007/s10858-012-9674-x · Cited by 196
“Conversely, co-operative sets of PTMs are frequently laid down in close proximity and allow direct synergistic or antagonistic cross talk between adjacent modification marks (Latham and Dent 2007; Kruse and Gu 2009; Martin et al. 2011).”
MEG3: an Oncogenic Long Non-coding RNA in Different Cancers
Al-Rugeebah, A., Alanazi, M., & Parine, N. R. (2019) · Pathology & Oncology Research · doi:10.1007/s12253-019-00614-3 · Cited by 195
Metadata
- Authors
- Kruse, J.-P., & Gu, W.
- Affiliations
- Columbia University (US)
- Corresponding author
- Gu, Wei
- ORCID
- Gu, Wei
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 137
- Issue
- 4
- Pages
- 609-622
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3737742
- OpenAlex
- W2025722611
- Cited by
- 1,610
- References
- 152
- Citations by year
- 2026: 31 · 2025: 49 · 2024: 52 · 2023: 57 · 2022: 81 · 2021: 98 · 2020: 75 · 2019: 73 · 2018: 100 · 2017: 98 · 2016: 102 · 2015: 108 · 2014: 142 · 2013: 127 · 2012: 128
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01ca085533-16)
- National Cancer Institute (R01-CA085533, R01CA131439, P01CA097403, R01CA104843, P01CA080058, R01CA098821, R01CA129627)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53 activation, p53 regulation, MDM2, MDMX, p53 stabilization, DNA binding, transcriptional activation, tumor suppressor
- MeSH terms
- Animals, Humans, Protein Processing, Post-Translational, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2
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