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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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Cites
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“p53 is subjected to a variety of posttranslational modifications that modulate its function as a tumor suppressor (1).”
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“Serine 15 phosphorylation increases both protein stability and transcriptional activity of p53, therefore activating p53 signaling.(14,18,19) Since genotoxic stress can create different types of DNA lesions or other forms of molecular damage, the coordinated activation of PIKKs responding to different lesions ensures…”
BackgroundCarlos, A. R., Escandell, J. M., Kotsantis, P., Suwaki, N., Bouwman, P., Badie, S., Folio, C., Benitez, J. J., Goméz-López, G., Pisano, D. G., et al. (2013) · Nature Communications · doi:10.1038/ncomms3697 · Cited by 47
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“It is worth mentioning here that although PFA abolishes the transcription-dependent function of p53, paradoxically, the level of p53 increases due to the absence of p53-induced negative feedback through MDM2 and p21 (27).”
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BackgroundTargeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice
Qu, J., Yang, S., Zhu, Y., Guo, T., Thannickal, V. J., & Zhou, Y. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20202033 · Cited by 45
The regulation of radiosensitivity by p53 and its acetylation
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Targeting tumor suppressor p53 for organ fibrosis therapy
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p53 acetylation enhances Taxol-induced apoptosis in human cancer cells
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p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance
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“It has been shown to enhance MDM2-mediated ubiquitination and degradation of p53, and repress p53-mediated transcription (reviewed by Marine et al., 2007; Kruse and Gu, 2009).”
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“…the association of p53 with histone acetyltransferases p300 and CBP and to regulate the transactivation properties of p53 [12,13]. phosphorylation has been shown to stimulate the association of p53 with acetyltransferases p300 and CBP and to regulate the transactivation properties of p53 [12,13].”
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“activity in response to cellular stress (1).”
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p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision
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SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways
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“N-terminal phosphorylation at Ser15 is thought to stabilize p53 by inhibiting the interaction between p53 and MDM2 42,60 .”
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“However, when the cell is exposed to various stressors, p53 undergoes post-translational modifications such as phosphorylation and acetylation, allowing its stabilization and activation (39).”
HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures
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“Both HR and LR HPV E6 proteins inactivate the transcription regulatory activities of another major tumor suppressor, p53 (7–10), abrogating its control over cell cycle arrest, DNA repair, apoptosis, or senescence (11).”
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“p53 is phosphorylated by a broad range of stress-activated kinases such as ATM, ATR, Chk1 and Chk2 while acetylation of p53 is carried out by transcriptional co-activators such as p300/CREB-binding protein (CBP) and p300/CBP-associated factor [16,17].”
BackgroundDECOD: fast and accurate discriminative DNA motif finding
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“In particular multiple lysines within the C-terminal domain (CTD) have been reported to undergo numerous modifications including acetylation, methylation, ubiquitination, and SUMOylation (Kruse and Gu, 2009).”
BackgroundRadioprotection by Hymenialdisine-Derived Checkpoint Kinase 2 Inhibitors
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MDM2/X inhibitors as radiosensitizers for glioblastoma targeted therapy
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“Hence, the above mechanisms form a autoregulatory loop to control the amount of p53 and MDM2 proteins (74, 79, 80).”
BackgroundTramutola, A., Pupo, G., Di Domenico, F., Barone, E., Arena, A., Lanzillotta, C., Broekaart, D., Blarzino, C., Head, E., Butterfield, D. A., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151105 · Cited by 40
“BothphosphorylationatSer 20 and acetylation of at Lys 382 residues within the C-terminal region of p53, are a determinant of its activity [31].”
Wen, S.-Y., Ng, S., Chiu, Y.-T., Tai, P.-Y., Chen, T., Chen, C.-J., Huang, C., & Kuo, W. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05945 · Cited by 42
Characterization of p53 expression in rainbow trout
Liu, M., Tee, C., Zeng, F., Sherry, J. P., Dixon, B., Bols, N. C., & Duncker, B. P. (2011) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2011.06.018 · Cited by 40
Hollingshead, M. G., Stockwin, L. H., Alcoser, S. Y., Newton, D. L., Orsburn, B. C., Bonomi, C. A., Borgel, S. D., Divelbiss, R. D., Dougherty, K., Hager, E. J., et al. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-393 · Cited by 40
“This tumor suppressor and master regulator of the cell cycle is frequently mutated or deleted in tumors [17,18].”
BackgroundChen, Y., Fujita, T., Zhang, D., Doan, H. Q., Pinkaew, D., Liu, Z., Wu, J., Koide, Y., Chiu, A., Lin, C. C.-J., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217836 · Cited by 40
Hu, L., Wang, J., Liu, Y., Zhang, Y., Zhang, L., Kong, R., Zheng, Z., Du, X., & Ke, Y. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.157842 · Cited by 41
Aberrant splicing of the DMP1 ‐ ARF ‐ MDM2 ‐p53 pathway in cancer
Inoue, K., & Fry, E. A. (2016) · International Journal of Cancer · doi:10.1002/ijc.30003 · Cited by 40
Wang, S., Qin, J., Ye, H., Wang, K., Shi, J., Ma, Y., Duan, Y., Song, C., Wang, X., Dai, L., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1452582 · Cited by 40
“p53 is a tumor suppressor protein related to apoptosis, transcriptional activation, DNA binding, cell metabolic regulation or autophagy.(20,21) Phosphatase and tensin homolog (PTEN) is another powerful tumor suppressor protein which has been known for regulating AKT kinase, downstream cell survival and growth response…”
BackgroundLiu, X., & Chen, J. (2019) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.9b00397 · Cited by 40
“Under prolonged genotoxic stress, p53-TAD accumulates phosphorylation at multiple sites, which reduces binding affinity to MDM2 and enhances binding to the CBP/p300, resulting in stabilization and activation of p53 58–62 .”
BackgroundDual regulation of p53 by the ribosome maturation factor SBDS
Hao, Q., Wang, J., Chen, Y., Wang, S., Cao, M., Lu, H., & Zhou, X. Y. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2393-4 · Cited by 40
Thotala, D. K., Hallahan, D. E., & Yazlovitskaya, E. M. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.94 · Cited by 40
“MDM2-mediated ubiquitination and the resulting proteasomal degradation of p53.(26) Stabilized p53 is subjected to a complex regulatory network to induce DNA binding and transcriptional”
USP7/HAUSP stimulates repair of oxidative DNA lesions
Khoronenkova, S. V., Dianova, I. I., Parsons, J. L., & Dianov, G. L. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq1210 · Cited by 40
Sasaki, K., Hamazaki, J., Koike, M., Hirano, Y., Komatsu, M., Uchiyama, Y., Tanaka, K., & Murata, S. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00216-10 · Cited by 40
“The activation of the ARF-p53 pathway was demonstrated by increased mRNA levels of ARF, p53, and molecules regulated by p53, such as p21, p63, Noxa, and Puma (18, 28, 42, 47, 72, 80) (Fig.”
BackgroundTargeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy
Yi, J., Tavana, O., Li, H., Wang, D., Baer, R. J., & Gu, W. J. (2023) · Nature Communications · doi:10.1038/s41467-023-37617-3 · Cited by 45
“More specifically, VPRBP bound a GST-fusion protein harboring the C-terminal intracellular domain (ICD, amino acids 231-290), but not theN-terminal (1-119) or middle (120-230) domains, of PD-L1 (Fig.”
BackgroundSelf-citationWang, X., Yang, J., Yang, W., Sheng, H., Jia, B., Peng, C., Xu, S., Hong, X., Jiang, C., Yang, Y., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.10.026 · Cited by 46
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“SIRT1 deacetylates p53 as a component of HDAC complexes [11], possibly by acting at major p53 acetylation sites to prevent p53-dependent transactivation of CDKN1A (which encodes p21) and Bcl-2-associated X protein (BAX) [12].”
BackgroundFrazier, D. P., Kendig, R. D., Kai, F., Maglic, D., Sugiyama, T., Morgan, R. L., Fry, E. A., Lagedrost, S. J., Sui, G., & Inoue, K. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2410 · Cited by 40
“Dmp1 is a critical transcriptional activator for Arf, and p19 (or p14) can, in turn, stabilize nucleoplasmic p53 by binding to Mdm2 and sequestering it in the nucleolus or by directly inhibiting the ubiquitin ligase activity of Mdm2 (6, 13).”
Perez, R. E., Knights, C. D., Sahu, G., Catania, J., Kolukula, V. K., Stoler, D. L., Graessmann, A., Ogryzko, V. V., Pishvaian, M. J., Albanese, C., et al. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22285 · Cited by 40
“O N C O G E N I C A C T I V I T Y O F P C A F I N T U M O R C E L L S E X P R E S S I N G previously shown that in the case of the wild-type protein, acetylation regulates p53 stability, DNA binding, and transcription (Kruse and Gu, 2009).”
BackgroundInfluentialHigh glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity
Garufi, A., & D’Orazi, G. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-014-0079-4 · Cited by 40
“P53 is the major tumor-suppressor that functions within an extensive signalling network [1].”
BackgroundRas and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program
Vasilaki, E., Morikawa, M., Koinuma, D., Mizutani, A., Hirano, Y., Ehata, S., Sundqvist, A., Kawasaki, N., Cedervall, J., Olsson, A., et al. (2016) · Science Signaling · doi:10.1126/scisignal.aag3232 · Cited by 39
“To gain insights into the role of the phosphorylation status of mutant p53 for its stability, we introduced a nonphosphorylatable alanine residue in each of the well-characterized serine phosphorylation sites in p53-R273H mutant (18).”
BackgroundOtub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria
Chen, Y., Wang, Y.-G., Li, Y., Sun, X., & Dai, M. (2016) · Oncotarget · doi:10.18632/oncotarget.14278 · Cited by 38
Loss of Genome Fidelity: Beta HPVs and the DNA Damage Response
Wendel, S. O., & Wallace, N. A. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02250 · Cited by 41
“Further, both ATM and ATR can stabilize p53 in response to DNA damage, causing p53-dependent DNA repair or apoptosis (Kruse and Gu, 2009; Cheng and Chen, 2010).”
BackgroundTanaka, T., Watanabe, M., & Yamashita, K. (2018) · Oncotarget · doi:10.18632/oncotarget.24611 · Cited by 46
Wu, H. H., Wang, B., Armstrong, S., Abuetabh, Y., Leng, S., Roa, W., Atfi, A., Marchese, A., Wilson, B. A., Sergi, C. M., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab081 · Cited by 39
A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network
Abou-Jaoudé, W., Madalena Chaves, A., & Gouzé, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017075 · Cited by 38
Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitryPreprint
Zhu, Y. Y., Regunath, K., Jacq, X., & Prives, C. L. (2013) · Genes & Development · doi:10.1101/gad.212258.112 · Cited by 39
“In response to various sources of cellular stress, multiple post-translational modifications, including phosphorylation, regulate the association between MDM2/MDMX and p53, and, in turn, such modifications lead to p53 stabilization and activation (Kruse and Gu 2009; Waning et al. 2010).”
Background
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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