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.
“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
Mdm2 and Mdmx have been detected at p53-responsive promoter elements in chromatin.
“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]
MDM2 is an E3 ubiquitin ligase that acts as a powerful inhibitor of tumor suppressor P53.
“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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HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2030930100 · Cited by 361 · see citing works
Stress Signals Utilize Multiple Pathways To Stabilize p53
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Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352 · see citing works
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The p53 response to DNA damage
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Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells
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Monoubiquitylation promotes mitochondrial p53 translocation
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Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate
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The Wip1 Phosphatase Acts as a Gatekeeper in the p53-Mdm2 Autoregulatory Loop
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A Novel Human SRB/MED-Containing Cofactor Complex, SMCC, Involved in Transcription Regulation
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Self-citationLatent and active p53 are identical in conformation.
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Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo
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Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus
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Critical role for Daxx in regulating Mdm2
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C-Terminal Ubiquitination of p53 Contributes to Nuclear Export
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Self-citationC-terminal modifications regulate MDM2 dissociation and nuclear export of p53
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The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression
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FBXO11 Promotes the Neddylation of p53 and Inhibits Its Transcriptional Activity
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An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors
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Mdmx as an essential regulator of p53 activity
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Kinetics of p53 Binding to Promoter Sites In Vivo
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Dual-Site Regulation of MDM2 E3-Ubiquitin Ligase Activity
Wallace, M., Worrall, E. G., Pettersson, S., Hupp, T. R., & Ball, K. L. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.05.029 · Cited by 171 · see citing works
hCAS/CSE1L Associates with Chromatin and Regulates Expression of Select p53 Target Genes
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SnapShot: p53 Posttranslational Modifications
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Self-citationAn essential function of the extreme C-terminus of MDM2 can be provided by MDMX
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ATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
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Hzf Determines Cell Survival upon Genotoxic Stress by Modulating p53 Transactivation
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Ser18 and 23 phosphorylation is required for p53‐dependent apoptosis and tumor suppression
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Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice
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DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation
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Cell Type- and Promoter-specific Roles of Ser18 Phosphorylation in Regulating p53 Responses
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The central region of HDM2 provides a second binding site for p53
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Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23
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KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis
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Inhibition of p53 degradation by Mdm2 acetylation
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Mutation of Mouse p53 Ser23 and the Response to DNA Damage
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MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53
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Self-citationMdm2 and Mdm4 Loss Regulates Distinct p53 Activities
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Binding of p53 to the Central Domain of Mdm2 Is Regulated by Phosphorylation
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The Role of Ubiquitination in the Direct Mitochondrial Death Program of p53
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Ubiquitination of p53 at Multiple Sites in the DNA-Binding Domain
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Crippling p53 activities via knock-in mutations in mouse models
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Facilitated search for specific genomic targets by p53 c-terminal basic DNA binding domain
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The ARF/Oncogene Pathway Activates p53 Acetylation within the DNA Binding Domain
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Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398 · see citing works
Self-citationIntrinsically disordered proteins in cellular signalling and regulation
Wright, P. E., & Dyson, H. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3920 · Cited by 2,371 · see citing works
Self-consumption: the interplay of autophagy and apoptosis
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Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
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“p53 levels are kept low under normal physiological conditions due to its interactions with E3 ubiquitin ligases, the best-studied of which is Hdm2 (also called Mdm2 in mouse), resulting in p53 nuclear export (following monoubiquitinylation), degradation (following polyubiquitinylation), and/or inhibition of its transa…”
BackgroundInfluentialEmerging Mechanisms and Disease Relevance of Ferroptosis
Stockwell, B. R., Jiang, X., & Gu, W. J. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.02.009 · Cited by 1,107 · see citing works
Self-citationP53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080 · see citing works
Identification of lysine succinylation as a new post-translational modification
Zhang, Z., Tan, M., Xie, Z., Dai, L., Chen, Y., & Zhao, Y. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.495 · Cited by 1,027 · see citing works
Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
Li, T., Kon, N., Jiang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., & Gu, W. (2012) · Cell · doi:10.1016/j.cell.2012.04.026 · Cited by 912 · see citing works
“In broad terms, p53 activities are controlled via protein levels, coactivator/corepressor recruitment, and a diverse array of posttranslational modifications that include acetylation, ubiquitination, phosphorylation, methylation, SUMOylation, and neddylation (Kruse and Gu, 2009).”
Self-citationHydrogen peroxide sensing, signaling and regulation of transcription factors
Marinho, H. S., Real, C., Cyrne, L., Soares, H., & Antunes, F. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.006 · Cited by 851 · see citing works
Drugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 723 · see citing works
Seyfried, T. N., & Shelton, L. M. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-7 · Cited by 656 · see citing works
“The cancer mutator phenotype was invoked to explain the large number of somatic mutations found in cancer, but mutations in the p53 caretaker gene are not expressed in all cancers nor does p53 deletion produce cancer in mice suggesting a more complicated involvement of this and other genome guardians in carcinogenesis…”
BackgroundZong, Z., Xie, F., Wang, S., Wu, X., Zhang, Z., Yang, B., & Zhou, F. (2024) · Cell · doi:10.1016/j.cell.2024.04.002 · Cited by 644 · see citing works
Mustafa, M., Ahmad, R., Tantry, I. Q., Ahmad, W., Siddiqui, S., Alam, M., Abbas, K., Moinuddin, Hassan, M. I., Habib, S., et al. (2024) · Cells · doi:10.3390/cells13221838 · Cited by 595 · see citing works
“Upon binding to the Apaf-1 protein in the cytoplasm, it forms the apoptosome, which activates initiator caspases, resulting in the activation of an apoptotic cascade [170,171].”
Transcriptional Regulation by P53
Beckerman, R., & Prives, C. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000935 · Cited by 569 · see citing works
“These modifications integrate the various cell signaling pathways that converge on the p53 protein (Sakaguchi et al. 1998; Bode and Dong 2004; Kruse and Gu 2009).”
BackgroundSignaling to p53: ribosomal proteins find their way
Zhang, Y., & Lu, H. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.024 · Cited by 591 · see citing works
“(Readers are referred to recent reviews for other extraribosomal functions of RPs [Warner and McIntosh, 2009] and downstream functions [Vousden and Prives, 2009] and regulations [Kruse and Gu, 2009] of p53.).”
BackgroundHeger, M., van Golen, R. F., Broekgaarden, M., & Michel, M. C. (2013) · Pharmacological Reviews · doi:10.1124/pr.110.004044 · Cited by 581 · see citing works
“dently of the ATM/ATR-mediated activation (Harper and Elledge, 2007; Kruse and Gu, 2009).”
BackgroundTumor Suppressive Functions of p53Preprint
Zilfou, J. T., & Lowe, S. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001883 · Cited by 572 · see citing works
“Numerous posttranslational modifications of p53 at various amino acids have been described, including phosphorylation, ubiquitination, acetylation, methylation, sumoylation, neddylation, glycosylation, and ribosylation (Carter and Vousden 2009; Kruse and Gu 2009).”
BackgroundInfluentialOxidative stress and pulmonary fibrosis
Cheresh, P., Kim, S.-J., Tulasiram, S., & Kamp, D. W. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.11.021 · Cited by 527 · see citing works
“Transcriptional activity of p53 is also regulated by interacting partners such as transcriptional coactivators or corepressors [108].”
Backgroundp53 post-translational modification: deregulated in tumorigenesis
Dai, C., & Gu, W. J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.09.002 · Cited by 523 · see citing works
Self-citationMicroRNAs in the p53 network: micromanagement of tumour suppression
Hermeking, H. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3318 · Cited by 518 · see citing works
The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury
Kriegel, A. J., Liu, Y., Fang, Y., Ding, X., & Liang, M. (2012) · Physiological Genomics · doi:10.1152/physiolgenomics.00141.2011 · Cited by 461 · see citing works
“The p53 transcription factor is important in controlling expression of genes that regulate cell growth, senescence, apoptosis, and genome integrity in response to stress (2, 39, 74, 90, 91).”
BackgroundMethionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells
Shiraki, N., Shiraki, Y., Tsuyama, T., Obata, F., Miura, M., Nagae, G., Aburatani, H., Kume, K., Endo, F., & Kume, S. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.017 · Cited by 514 · see citing works
Oncogenes and Tumor Suppressor GenesPreprint
Lee, E. Y., & Muller, W. J. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003236 · Cited by 515 · see citing works
“active and its deletion results in embryonic lethality (reviewed in Donehower and Lozano 2009; Kruse and Gu 2009).”
BackgroundUnderstanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 519 · see citing works
Self-citationPhysicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)
Theillet, F., Binolfi, A., Frembgen-Kesner, T., Hingorani, K. S., Sarkar, M., Kyne, C., Li, C., Crowley, P. B., Gierasch, L. M., Pielak, G. J., et al. (2014) · Chemical Reviews · doi:10.1021/cr400695p · Cited by 504 · see citing works
Maiuri, M. C., Galluzzi, L., Morselli, E., Kepp, O., Malik, S. A., & Kroemer, G. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.12.001 · Cited by 498 · see citing works
“However, in response to adverse conditions including genotoxic, hypoxic, and oncogenic stress, p53 rapidly undergoes reversible post-translational modifications that allow for its stabilization [6].”
BackgroundPosttranslational Modification of p53: Cooperative Integrators of FunctionPreprint
Meek, D. W., & Anderson, C. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000950 · Cited by 487 · see citing works
“Mechanistically, the acetylated lysines are thought to participate in mediating “antirepression” (Tang et al. 2008; Kruse and Gu 2009).”
BackgroundThe Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents
Zhou, J., Kang, Y., Chen, L., Wang, H., Liu, J., Zeng, S., & Yu, L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00343 · Cited by 481 · see citing works
Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression
Wang, S.-J., Li, D., Ou, Y., Jiang, L., Chen, Y., Zhao, Y., & Gu, W. J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.022 · Cited by 463 · see citing works
“…include p53 protein stability, co-activator and inhibitor recruitment, and a diverse array of posttranslational modifications, including acetylation, ubiquitination, phosphorylation, methylation, sumoylation, and neddylation (Eischen and Lozano, 2014; Gannon and Jones, 2012; Kruse and Gu, 2009).”
BackgroundSelf-citationThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
“This transcriptional antagonism can take place within the nucleus, as Mdm2 and Mdmx have been detected at p53-responsive promoter elements in chromatin [2].”
BackgroundMetabolic Regulation by p53 Family Members
Berkers, C. R., Maddocks, O. D. K., Cheung, E. C., Mor, I., & Vousden, K. H. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.019 · Cited by 443 · see citing works
Roles of BCL6 in normal and transformed germinal center B cells
Basso, K., & Dalla‐Favera, R. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01112.x · Cited by 431 · see citing works
“Two distinct pathways are involved in acetylationmediated activation of TP53, as shown by the activity of the class I and II histone deacetylase (HDAC) inhibitor trichostatin A (TSA) and class III histone deacetylase or sirtuin inhibitor nicotinamide (NIA) in enforcing TP53 activity (59, 60).”
BackgroundRole of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer
Liu, G., Pei, F., Yang, F., Li, L., Amin, A. D., Liu, S., Buchan, J. R., & Cho, W. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020367 · Cited by 424 · see citing works
“In addition, some p53 mutations, including L22Q and W23S, retain its pro-apoptotic properties, whereas other mutations, including L194F and R280K, lose this, which may augment tumorigenesis and disease progression [51,56].”
Backgroundp53 modifications: exquisite decorations of the powerful guardian
Liu, Y., Tavana, O., & Gu, W. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz060 · Cited by 392 · see citing works
Self-citationBarr, A. R., Cooper, S., Heldt, F. S., Butera, F., Stoy, H., Mansfeld, J., Novák, B., & Bakal, C. (2017) · Nature Communications · doi:10.1038/ncomms14728 · Cited by 403 · see citing works
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“The work must be attributed back to the original author and commercial use is not permitted without specific permission.”
BackgroundBao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
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“…diffusion that helps p53 hone in on its response elements, as well as undergoing extensive posttranslational modifications that modulate p53 stabilization and sequence-specific DNA binding (Kruse and Gu, 2009; Laptenko and Prives, 2006; Liu and Kulesz-Martin, 2006; Murray-Zmijewski et al., 2008).”
BackgroundThe Origin of Allosteric Functional Modulation: Multiple Pre-existing Pathways
del Sol, A., Tsai, C., Ma, B., & Nussinov, R. (2009) · Structure · doi:10.1016/j.str.2009.06.008 · Cited by 365 · see citing works
“For the p53, specific post-translational phophorylation events are well documented to regulate its functions (Kruse and Gu, 2009).”
BackgroundCurcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects
Hassan, F., Rehman, M. S.-U., Khan, M. S., Ali, M. A., Javed, A., Nawaz, A. S., & Yang, C. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00514 · Cited by 369 · see citing works
The Tumor Suppressor p53: From Structures to Drug DiscoveryPreprint
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MALAT1: a druggable long non-coding RNA for targeted anti-cancer approaches
Amodio, N., Raimondi, L., Juli, G., Stamato, M. A., Caracciolo, D., Tagliaferri, P., & Tassone, P. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0606-4 · Cited by 351 · see citing works
Gene Copy-Number Alterations: A Cost-Benefit Analysis
Tang, Y.-C., & Amon, A. (2013) · Cell · doi:10.1016/j.cell.2012.11.043 · Cited by 348 · see citing works
“Indeed, p53 inactivation is a major contributor to tumorigenesis (Dai and Gu, 2010; Kruse and Gu, 2009; Toledo and Wahl, 2006).”
The Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor
Manfredi, J. J. (2010) · Genes & Development · doi:10.1101/gad.1941710 · Cited by 344 · see citing works
“However, upon p53 activation by DNA damage and subsequent post-translational modification of both partners, the interaction between p53 and Mdm2 is disrupted (see Kruse and Gu 2009; Vousden and Prives 2009; Marine and Lozano 2010; Wade et al. 2010).”
BackgroundInfluentialTwo-phase dynamics of p53 in the DNA damage response
Zhang, X.-P., Liu, F., & Wang, W. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100600108 · Cited by 333 · see citing works
“First, p53 is primarily modified (such as phosphorylation at Ser-15 and Ser-20) and accumulates in pulses to induce protective cell cycle arrest for repairable DNA damage; it is further modified (such as phosphorylation at Ser-46) and fully activated to induce apoptosis for irreparable DNA damage (35).”
Backgroundp53 Acetylation: Regulation and Consequences
Reed, S. M., & Quelle, D. E. (2014) · Cancers · doi:10.3390/cancers7010030 · Cited by 330 · see citing works
“Alternatively, given the redundancies in p53 regulation [31,32], phosphorylation of other N-terminal sites may simply compensate for the loss of S18 phosphorylation and support C-terminal acetylation.”
BackgroundInfluentialTumor-Suppressor Functions of the TP53 PathwayPreprint
Aubrey, B. J., Strasser, A., & Kelly, G. L. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026062 · Cited by 331 · see citing works
“…system of posttranslational modifications, including phosphorylation, acetylation, and ubiquitination, which impact TP53 protein binding to specific sites in the DNA, protein turnover, and interaction with other proteins that affect TP53 protein transcriptional function (Kruse and Gu 2009).”
BackgroundThe next level of complexity: Crosstalk of posttranslational modifications
Venne, A. S., Kollipara, L., & Zahedi, R. P. (2013) · PROTEOMICS · doi:10.1002/pmic.201300344 · Cited by 325 · see citing works
“Many studies postulated that in p53 diverse PTMs might occur at identical amino acid positions [39,40].”
BackgroundThe Role of p53 Signaling in Colorectal Cancer
Liebl, M. C., & Hofmann, T. G. (2021) · Cancers · doi:10.3390/cancers13092125 · Cited by 332 · see citing works
“ATM, ATR, and DNA-PKcs phosphorylate p53 at Ser15, whereas the ATM/ATR substrates CHK1 and CHK2 phosphorylate p53 at Ser20 (Figure 2A) [25].”
BackgroundRedox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy
Marengo, B., Nitti, M., Furfaro, A. L., Colla, R., Ciucis, C. D., Marinari, U. M., Pronzato, M. A., Traverso, N., & Domenicotti, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/6235641 · Cited by 319 · see citing works
“It is kept at low levels by several E3 ubiquitin ligases, such as Mdm2, responsible for its degradation [178], and it is stabilized by posttranslational modifications such as phosphorylation, acetylation, and methylation [179, 180].”
BackgroundNRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression
Chen, D., Tavana, O., Chu, B., Erber, L. N., Chen, Y., Baer, R. J., & Gu, W. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.009 · Cited by 321 · see citing works
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The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage
Zhang, A., Zhou, N., Huang, J., Liu, Q., Fukuda, K., Ma, D., Lü, Z., Bai, C., Watabe, K., & Mo, Y. (2012) · Cell Research · doi:10.1038/cr.2012.164 · Cited by 301 · see citing works
Emerging roles for chromatin as a signal integration and storage platform
Badeaux, A. I., & Shi, Y. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3545 · Cited by 291 · see citing works
A positive feedback between p53 and miR-34 miRNAs mediates tumor suppressionPreprint
Okada, N., Lin, C., Ribeiro, M. C., Biton, A., Lai, G., He, X., Bu, P., Vogel, H. S., Jablons, D. M., Keller, A., et al. (2014) · Genes & Development · doi:10.1101/gad.233585.113 · Cited by 297 · see citing works
“While Mdm2 acts as an ubiquitin E3 ligase that promotes p53 protein degradation via polyubiquitination (Eischen and Lozano 2009; Kruse and Gu 2009), Mdm4 does not possess E3 ubiquitin ligase activity by itself.”
BackgroundThe multiple levels of regulation by p53 ubiquitination
Lee, J. T., & Gu, W. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.77 · Cited by 289 · see citing works
“p53 is then activated through various kinases and acetyltransferases allowing for the binding of p53 to transcriptional targets, such as p21, PUMA, BAX, and Noxa (Figure 3).(12,17,42)”
Self-citationMolecular mechanisms of etoposide.
Montecucco, A., Zanetta, F., & Biamonti, G. (2015) · EXCLI journal · doi:10.17179/excli2015-561 · Cited by 293 · see citing works
“The interaction with NLK stabilizes p53 through the inhibition of the MDM2-mediated degradation of the protein, mediated by the ubiquitin-proteasome system (Zhang et al., 2014; Kruse and Gu, 2009).”
BackgroundKrifka, S., Spagnuolo, G., Schmalz, G., & Schweikl, H. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.03.019 · Cited by 289 · see citing works
Regulation of the p53 response and its relationship to cancer
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Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis
Wang, S., & Wang, Y. (2013) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2013.07.003 · Cited by 283 · see citing works
Negative regulation of the tumor suppressor p53 gene by microRNAs
Kumar, M., Lu, Z., Takwi, A. A., Chen, W., Callander, N. S., Ramos, K. S., Young, K. H., & Li, Y. (2010) · Oncogene · doi:10.1038/onc.2010.457 · Cited by 284 · see citing works
The impact of acetylation and deacetylation on the p53 pathway
Brooks, C. L., & Gu, W. J. (2011) · Protein & Cell · doi:10.1007/s13238-011-1063-9 · Cited by 279 · see citing works
“A number of post-translational modifications can occur in p53 that have critical effects on its stability and function, including phosphorylation, acetylation, sumoylation, neddylation, and methylation (Kruse and Gu, 2009a).”
BackgroundInfluentialSelf-citationThe functional diversity of protein lysine methylation
Lanouette, S., Mongeon, V., Figeys, D., & Couture, J. (2014) · Molecular Systems Biology · doi:10.1002/msb.134974 · Cited by 274 · see citing works
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Regulation of autophagy by stress-responsive transcription factors
Pietrocola, F., Izzo, V., Niso‐Santano, M., Vacchelli, E., Galluzzi, L., Maiuri, M. C., & Kroemer, G. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.05.008 · Cited by 270 · see citing works
Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer
Kędzierska, H., & Piekiełko‐Witkowska, A. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.03.013 · Cited by 261 · see citing works
The complexity of p53-mediated metabolic regulation in tumor suppression
Liu, Y., & Gu, W. J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.010 · Cited by 260 · see citing works
Self-citationDNA damage kinase signaling: checkpoint and repair at 30 years
Lanz, M. C., Dibitetto, D., & Smolka, M. B. (2019) · The EMBO Journal · doi:10.15252/embj.2019101801 · Cited by 259 · see citing works
“…by all the DNA damage signaling kinases, eliciting a p53-dependent transcriptional response that impacts the DNA damage response (reviewed in Kruse & Gu, 2009). p53-mediated expression of the CDK inhibitor protein p21 represents the primary mechanism by which p53 blocks progression through…”
Robbiani, D. F., Bunting, S. F., Feldhahn, N., Bothmer, A., Camps, J., Deroubaix, S., McBride, K. M., Klein, I. A., Stone, G. A., Eisenreich, T., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.11.007 · Cited by 258 · see citing works
“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 · see citing works
“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 · see citing works
“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 247 · see citing works
“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 · see citing works
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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 234 · see citing works
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 234 · see citing works
“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 233 · see citing works
Jang, I., Henriques, R., Seo, H. S., Nagatani, A., & Chua, N. (2010) · The Plant Cell · doi:10.1105/tpc.109.072520 · Cited by 228 · see citing works
“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 224 · see citing works
“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 225 · see citing works
“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 224 · see citing works
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 219 · see citing works
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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 · see citing works
“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 213 · see citing works
“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 · see citing works
“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 210 · see citing works
“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 206 · see citing works
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 200 · see citing works
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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 · see citing works
“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 202 · see citing works
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 199 · see citing works
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Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis
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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 · see citing works
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 188 · see citing works
“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 190 · see citing works
- 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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