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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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“Quantitative real-time PCR (qRT–PCR) assays were performed for measurement of the expression levels of pri-and pre-miRNAs as described previously (Kruse and Gu, 2009).”
Self-citationDai, L., Li, J., Ortega, R., Qian, W., Casiano, C. A., & Zhang, J.-Y. (2014) · Journal of Immunology Research · doi:10.1155/2014/827827 · Cited by 36
“In addition to cylcin B1, we have also detected 14 other TAAs, including nine oncoproteins such as three IMP proteins (IMP1, IMP2/p62, and IMP3/Koc) [23], CIP2A/p90 [24], RalA [25], c-Myc [26], survivin [27], 14-3-3 ζ [28], and MDM2 [29], four tumor suppressors such as p53 [30], CAPERα/HCC1 [20], p16 [31], and NPM1 [3…”
BackgroundLouwen, F., & Yuan, J. (2013) · Oncotarget · doi:10.18632/oncotarget.1096 · Cited by 38
“Moreover, phosphorylation of S15 in p53 is required for blocking its interaction with MDM2 and contributes to its stabilization [61].”
BackgroundInfluentialSwitching on p53: an essential role for protein phosphorylation?
Loughery, J., & Meek, D. W. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.1 · Cited by 39
“Moreover, if induction occurs via the “anti-repression” model [48], where p53 is anchored to promoters and repressed in situ by MDM2 and MDM4, this could be used to selectively or preferentially activate certain genes if it were possible to simultaneously disengage MDM2/MDM4 and regulate the access of the signalling e…”
InfluentialOu, W., Zhu, J., Eilers, G., Li, X., Kuang, Y., Liu, L., Mariño‐Enríquez, A., Yan, Z., Li, H., Meng, F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3230 · Cited by 38
G9a stimulates CRC growth by inducing p53 Lys373 dimethylation-dependent activation of Plk1
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“p53 is a transcription factor that activates and/or represses its target genes, indicating the presence of a highly complex regulatory network for fine-tuning the responses of p53 to different stress signals [29].”
BackgroundJung, J. H., Lee, H., Kim, J., Sim, D. Y., Ahn, H., Kim, B., Chang, S., & Kim, S. (2019) · Cancers · doi:10.3390/cancers11040582 · Cited by 38
“It is well documented that p53 plays an important role in cancer cells as a tumor suppressor [21] and is closely associated with c-Myc downregulation [22].”
BackgroundOn the role of p53 in the cellular response to aneuploidy
Narkar, A., Johnson, B. A., Bharne, P., Zhu, J., Padmanaban, V., Biswas, D., Fraser, A. K., Iglesias, P. A., Ewald, A. J., & Li, R. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108892 · Cited by 34
“p53 is known to be regulated predominantly by posttranslational modifications that affect its stability or nuclear accumulation (Haupt et al., 1997; Kruse and Gu, 2009; Oren, 1999).”
Backgroundp73 as a Pharmaceutical Target for Cancer Therapy
Bisso, A., Collavin, L., & Sal, G. D. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222667 · Cited by 41
“From a molecular point of view, p53 is a transcription factor and its activation/inactivation in response to stress depends on a complex repertoire of post-translational modifications and interactions with regulatory cofactors (reviewed in [2, 3]).”
BackgroundGaric, A., Berres, M. E., & Smith, S. M. (2014) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12457 · Cited by 38
“MDM2 silencing by these unchaparoned ribosomal proteins causes p53 accumulation and p53-mediated apoptosis (Fumagalli and Thomas, 2011; Kruse and Gu, 2009).”
BackgroundArsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes
Herbert, K. J., Holloway, A. F., Cook, A. L., Chin, P. S., & Snow, E. T. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.09.012 · Cited by 39
“Mild p53 activation promotes cell cycle arrest and DNA repair (Chen et al., 1996), whereas further increased induction of activated p53 triggers apoptotic signalling and cell death (Fridman and Lowe, 2003; Kruse and Gu, 2009; Purvis et al., 2012).”
BackgroundPharmacological Activation of p53 in Cancer Cells
Athar, M., Elmets, C. A., & Kopelovich, L. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222595 · Cited by 40
Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells
Wirries, A., BREYER, S., Quint, K., Schobert, R., & Ocker, M. (2010) · Experimental and Therapeutic Medicine · doi:10.3892/etm_00000058 · Cited by 38
“…was observed in hepG2 cells, this up-regulation was not observed at the protein level, indicating a post-transcriptional processing of p53 mrna (18). the observed growth inhibition and redistribution of cells to the S/G 2 phase was confirmed using PCR based on the observed strong…”
Watanabe, K., Shibuya, S., Koyama, H., Ozawa, Y., Toda, T., Yokote, K., & Shimizu, T. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140610998 · Cited by 37
“ATM phosphorylates both p53 at Ser(15) (mouse Ser(18)) and MDM2, an endogenous E3-ligase for p53, at Ser(395), resulting in an impairment of MDM2-mediated p53 degradation [22].”
BackgroundQuintens, R., Verreet, T., Janssen, A., Neefs, M., Leysen, L., Michaux, A., Verslegers, M., Samari, N., Pani, G., Verheyde, J., et al. (2015) · Biology Open · doi:10.1242/bio.20149969 · Cited by 40
“KEY WORDS: Alternative splicing, Development, Embryonic brain, Ionizing radiation, Neuronal differentiation, p53 targets”
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Gradual reduction in rRNA transcription triggers p53 acetylation and apoptosis via MYBBP1A
Kumazawa, T., Nishimura, K., Katagiri, N., Hashimoto, S., Hayashi, Y., & Kimura, K. (2015) · Scientific Reports · doi:10.1038/srep10854 · Cited by 38
SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity
Mizuguchi, Y., Specht, S. M., Lunz, J. G., Isse, K., Corbitt, N., Takizawa, T., & Demetris, A. J. (2012) · BMC Molecular Biology · doi:10.1186/1471-2199-13-20 · Cited by 37
“ATM/ ATR/DNAPK), and Chk1/Chk2 is regarded as the first crucial step in p53 stabilization [3].”
BackgroundOno, W., Hayashi, Y., Yokoyama, W., Kuroda, T., Kishimoto, H., Ito, I., Kimura, K., Akaogi, K., Waku, T., & Yanagisawa, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.474049 · Cited by 39
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“A cell’s fate can be decided by specific phosphorylation of p53 (26).”
BackgroundMazouzi, A., Stukalov, A., Müller, A. C., Chen, D., Wiedner, M., Prochazkova, J., Chiang, S., Schuster, M. K., Breitwieser, F. P., Pichlmair, A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.077 · Cited by 36
“Efficient depletion of CRMP2 also triggered an increase in phosphorylation of TP53 at S15 upon APH treatment, indicative of increased apoptosis and/or cell-cycle arrest (Kruse and Gu, 2009; Shaw, 1996) (Figure 6D).”
BackgroundZheng, L., Cao, S., Zhou, H., Ling, H., Zhang, S., & Cao, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125727 · Cited by 36
Dihydromyricetin induces cell cycle arrest and apoptosis in melanoma SK-MEL-28 cells
Zeng, G., Liu, J., Chen, H., Liu, B., Zhang, Q., Li, M., & Zhu, R. (2014) · Oncology Reports · doi:10.3892/or.2014.3160 · Cited by 36
Ueno, T., Endo, S., Saito, R., Hirose, M., Hirai, S., Suzuki, H., Yamato, K., & Hyodo, I. (2014) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504013x13854886566598 · Cited by 36
Regulation of DNA damage responses and cell cycle progression by hMOB2
Gómez, V., Gündoğdu, R., Gómez-Ferrer, M., Hoa, L., Panchal, N., O’Driscoll, M., & Hergovich, A. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.11.016 · Cited by 38
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“Background As an important tumor suppressor, TP53 protein level is low or undetectable in normal cells, but diverse forms of stress may trigger its production, resulting in either cell cycle arrest or apoptotic cell death [1,2].”
Chen, B., Longtine, M. S., & Nelson, D. M. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00218.2013 · Cited by 38
“The p53 pathway is regulated by multiple mechanisms, including changes in protein stability mediated by MDM2 and MDMX, changes in transcription, and a multitude of regulated phosphorylations (21, 22, 25).”
BackgroundLi, X., Wang, X., Wang, X., Liu, S.-H., Ding, X., Chen, G., & Lu, Y. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.737056 · Cited by 36
“Upon the stress, P53 is modified by multiple post-transcriptional mechanisms, such as phosphorylation at serine(Ser) 15 by the serine threonine kinase ataxia-telangiectasia mutated (ATM), which leads to its dissociation from its negative regulator MDM2, followed by the accumulation and activation of P53 (19).”
BackgroundNegative auto-regulators trap p53 in their web
Zhou, X. Y., Cao, B., & Lu, H. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx001 · Cited by 37
Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
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“Ever since, a range of lysine residues have been identified across the domains of p53, with majority of acetylated lysine residues being concentrated in the C-terminus region of p53 (Brooks and Gu, 2011; Gu and Zhu, 2012; Gu and Roeder, 1997; Kruse and Gu, 2009).”
BackgroundEpigenetic changes and their implications in autoimmune hepatitis
Czaja, A. J. (2018) · European Journal of Clinical Investigation · doi:10.1111/eci.12899 · Cited by 36
Nazim, U. M., & Park, S. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3994 · Cited by 36
“Previous studies have established a major role of p53 in the regulation of DNA repair, cell cycle arrest, apoptosis, senescence and autophagy (27-29).”
Li, W., Peng, X., Lang, J., & Xu, C. S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00631 · Cited by 36
p53 regulated senescence mechanism and role of its modulators in age-related disorders
Pawge, G., & Khatik, G. L. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114651 · Cited by 38
The transcription factor CREBZF is a novel positive regulator of p53
López-Mateo, I., Villaronga, M. Á., Llanos, S., & Belandia, B. (2012) · Cell Cycle · doi:10.4161/cc.22133 · Cited by 36
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Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis
Yang, Y., Wang, C., Zhang, P., Gao, K., Wang, D., Yu, H., Zhang, T., Jiang, S., Hexige, S., Hong, Z., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.338996 · Cited by 36
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“In normal tissues, p53 is maintained at extremely low levels by rapid protein turnover that is mediated by its negative regulator murine double minute 2 (Mdm2) E3 ubiquitin ligase (22).”
BackgroundInfluentialZhang, G., An, Y.-F., Lü, X., Zhong, H., Zhu, Y., Wu, Y., Ma, F.-E., Yang, J., Liu, Y., Zhou, Z., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.669978 · Cited by 36
“p53 activation is a common response to cellular stresses (32), especially in small molecule-induced p53 activation, with DNA damage as a main cause for p53 activation (33).”
BackgroundChallenges and opportunities in cell expansion for cultivated meat
Hauser, M., Zirman, A., Rak, R., & Nachman, I. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1315555 · Cited by 37
The p53-Mdm2 Loop: A Critical Juncture of Stress Response
Levav-Cohen, Y., Goldberg, Z., Tan, K. H., Alsheich-Bartok, O., Zuckerman, V., Haupt, S., & Haupt, Y. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_9 · Cited by 38
“Mdm2 is a phosphoprotein, that is subject to both phosphorylation and dephosphorylation of specific sites in response to DNA damage [119, 120] (also reviewed in [121–123]).”
BackgroundGanguly, D., & Chen, J. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004247 · Cited by 38
“Cellular stresses such as DNA damage, initiate a cascade of phosphorylation events that stabilize and activate the p53 protein [27].”
BackgroundBattle Against Cancer: An Everlasting Saga of p53
Hao, Q., & Cho, W. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151222109 · Cited by 38
“and acetylation by p300/CBP, PCAF, hMOF and Tip60 [35–39], which disrupts the interaction of MDM2 and p53, consequently leading to p53 activation [40].”
BackgroundShin, C.-H., Lee, M.-G., Han, J., Jeong, S.-I., Ryu, B., & Chi, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700861114 · Cited by 35
“To define apoptotic signaling pathways controlled by XAF1–MT2A antagonism, we examined the effect of XAF1–MT2A antagonism on the intracellular zinc level and p53 protein, a representative apoptotic factor the conformation of which is regulated in a highly zinc-dependent manner (34).”
BackgroundXi, Y., Wang, W., Wang, L., Pan, J., Cheng, Y., Shen, F., & Huang, Z. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.07.011 · Cited by 37
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KDM5A Regulates a Translational Program that Controls p53 Protein Expression
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Emerging roles of long non-coding RNAs in the p53 network
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The role of NUMB/NUMB isoforms in cancer stem cells
Choi, H. Y., Seok, J., Kang, G., Lim, K. M., & Cho, S. (2021) · BMB Reports · doi:10.5483/bmbrep.2021.54.7.048 · Cited by 35
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“Ser15 phosphorylation is important for dissociation of the E3 ligase MDM2 and accumulation of p53 via stabilization (Kruse and Gu, 2009; Toledo and Wahl, 2006).”
BackgroundHarmonic Oscillations in Homeostatic Controllers: Dynamics of the p53 Regulatory System
Jolma, I. W., Ni, X. Y., Rensing, L., & Ruoff, P. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.11.013 · Cited by 35
Cytoplasmic localization of DGKζ exerts a protective effect against p53-mediated cytotoxicity
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“These specificities are achieved through posttranslational modifications that are dynamically deposited on p53 in a context-specific manner (Kruse and Gu, 2009).”
BackgroundInfluentialOda, T., Gotoh, N., Kasamatsu, T., Handa, H., Saitoh, T., & Sasaki, N. (2023) · Cell Proliferation · doi:10.1111/cpr.13398 · Cited by 33
Targeting mutant p53 stabilization for cancer therapy
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“Post-translational modifications inhibit MDM2-mediated p53 ubiquitination and enhance p53 stability and activity, allowing p53 to be highly expressed and exert tumor suppressive functions (Kruse and Gu, 2009; Levine and Oren, 2009).”
BackgroundXanthohumol Induces Different Cytotoxicity and Apoptotic Pathways in Malignant and Normal Astrocytes
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“Both mechanisms are regulated by tumour suppressor protein p53, the expression of which differs in many tumour cells due to numerous translational and post-translational alterations (Kruse and Gu, 2009).”
BackgroundNovel Nucleolar Pathway Connecting Intracellular Energy Status with p53 Activation
Kumazawa, T., Nishimura, K., Kuroda, T., Ono, W., Yamaguchi, C., Katagiri, N., Tsuchiya, M., Masumoto, H., Nakajima, Y., Murayama, A., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209916 · Cited by 34
Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xLratio
Goloudina, A. R., Mazur, S. J., Appella, E., Garrido, C., & Demidov, O. N. (2012) · Cell Cycle · doi:10.4161/cc.19901 · Cited by 37
“p53 is a major regulator of cellular stress responses and induces genes involved in cell cycle arrest, DNA repair, senescence and apoptosis.(3) The tumor suppressor function of p53 results primarily from its ability to promote apoptosis through a combination of transcription-dependent and -independent mechanisms.”
BackgroundHe, X., Liu, F., Yan, J., Zhang, Y., Yan, J., Shang, H., Dou, Q., Zhao, Q., & Song, Y. (2015) · Scientific Reports · doi:10.1038/srep08705 · Cited by 34
Nair, B. C., Krishnan, S. R., Sareddy, G. R., Mann, M., Xu, B., Natarajan, M., Hasty, P., Brann, D. W., TEKMAL, R. R., & Vadlamudi, R. K. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.55 · Cited by 35
SMG7 is a critical regulator of p53 stability and function in DNA damage stress response
Luo, H., Cowen, L. E., Yu, G., Jiang, W. G., & Tang, Y. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.42 · Cited by 33
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“For example, p53 is a well-known tumor suppressor and frequently mutated in cancer (Freed-Pastor and Prives, 2012; Isobe et al., 1986; Kruse and Gu, 2009).”
BackgroundJochemsen, A. G., & Shiloh, Y. (2010) · Cell · doi:10.1016/j.cell.2010.01.034 · Cited by 34
“USP7 regulates p53 in a dual fashion: it stabilizes p53 directly by deubiquitinating it and simultaneously deubiquitinates and stabilizes Mdm2 and Mdmx, thereby helping to keep the amount of p53 in check (Kruse and Gu, 2009; Meulmeester et al., 2005).”
BackgroundTargeted Molecular Therapy for Neuroblastoma: The ARF/MDM2/p53 Axis
Kim, E. S., & Shohet, J. M. (2009) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djp376 · Cited by 34
Chantarawong, W., Kuncharoen, N., Tanasupawat, S., & Pithi Chanvorachote, B. (2019) · Nutrition and Cancer · doi:10.1080/01635581.2019.1610183 · Cited by 34
“The tumor suppressor p53 protein, encoded by TP53 gene, has an important role in the regulation of cell cycle, DNA repair and apoptosis (40).”
BackgroundZhang, Q., Xiao, H., Chai, S. C., Hoang, Q. Q., & Lu, H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.277012 · Cited by 34
Zhao, Q., Fan, J., Wei, H., Li, L., & Wu, M. (2012) · SpringerPlus · doi:10.1186/2193-1801-1-65 · Cited by 33
“…suppressor gene, mutated in up to 50% of cancers (Royds and Iacopetta 2006). p53 can be activated by various signals, such as irradiation or chemical induced DNA damage, abnormal oncogene expression, microtubule inhibitors and other stress conditions (Royds and Iacopetta 2006; Kruse and Gu 2009).”
The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination
Cubillos‐Rojas, M., Schneider, T., Hadjebi, O., Pedrazza, L., de Oliveira, J. R., Vives, F. L., Guénet, J., Duran, J., de Anta, J. M., Alcántara, S., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11270 · Cited by 32
Chen, Z., Cao, Z., Zhang, W., Gu, M., Zhou, Z., Li, B., Li, J., Tan, E., & Zeng, L. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx337 · Cited by 34
FBXL6 degrades phosphorylated p53 to promote tumor growth
Li, Y., Cui, K., Zhang, Q., Lin, X., Lin, X., Tang, Y., Prochownik, E. V., & Li, Y. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00739-6 · Cited by 34
DNA repair pathways and their roles in drug resistance for lung adenocarcinoma
Kara, A., Özgür, A., Nalbantoğlu, S., & Karadağ, A. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06314-z · Cited by 35
“These signals activate TP53 protein via post-translational modifications such as phosphorylation, ubiquitination, and acetylation [29].”
BackgroundATM and KAT5 safeguard replicating chromatin against formaldehyde damage
Ortega-Atienza, S., Wong, V. C., DeLoughery, Z. J., Łuczak, M. W., & Zhitkovich, A. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv957 · Cited by 33
The DNA damage response: The omics era and its impact
Derks, K., Hoeijmakers, J. H. J., & Pothof, J. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.03.008 · Cited by 38
Miyajima, C., Inoue, Y., & Hayashi, H. (2015) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b15-00003 · Cited by 33
Liu, J., Liu, Z., Wang, D., Li, M., Wang, S., Wang, R., Chen, J., Wang, Y., & Yang, D. (2011) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2011.02.026 · Cited by 33
p53 localizes to intranucleolar regions distinct from the ribosome production compartments
Krüger, T., & Scheer, U. (2010) · Journal of Cell Science · doi:10.1242/jcs.062398 · Cited by 33
“p14ARF can rescue p53 from degradation either by direct inhibition of MDM2 in the nucleoplasm or by sequestration of MDM2 in the nucleolus (Kruse and Gu, 2009).”
BackgroundCurrent Understanding of the Emerging Role of Prolidase in Cellular Metabolism
Misiura, M., & Miltyk, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165906 · Cited by 33
“p53, as the guardian of the genome, protects cells from uncontrolled cell division that may lead to proliferation of mutated cells and promote tumor progression [40].”
BackgroundFragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2
Silva-Santisteban, M. C., Westwood, I. M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, E., Richards, M., Mirza, A., Oliver, A. W., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065689 · Cited by 31
Lin, K., Farahani, M., Yang, Y., Johnson, G. G., Oates, M., Atherton, M., Douglas, A., Kalakonda, N., & Pettitt, A. R. (2014) · British Journal of Haematology · doi:10.1111/bjh.13043 · Cited by 32
“This lack of correlation between TP53 mRNA and TP53 protein levels is likely to reflect the dominant role of post-translational regulation in determining TP53 protein expression (Kruse & Gu, 2009).”
BackgroundSilencing of CD24 Enhances the PRIMA-1–Induced Restoration of Mutant p53 in Prostate Cancer Cells
Zhang, W., Yi, B., Wang, C., Chen, D., Bae, S., Wei, S., Guo, R., Lu, C., Nguyen, L. L. H., Yang, W., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1927 · Cited by 32
“CD24 is a partner of mutant p53 protein in tumor progression of prostate cancer WT p53 proteins are unstable (25), but missense mutant p53 proteins often accumulate at high levels in tumor tissues (37).”
BackgroundUBE4B targets phosphorylated p53 at serines 15 and 392 for degradation
Du, C., Wu, H., & Leng, R. P. (2015) · Oncotarget · doi:10.18632/oncotarget.6555 · Cited by 32
Chang, S., Shan, X., Li, X., Fan, W., Zhang, S. Q., Zhang, J., Jiang, N., Ma, D., & Mao, Z. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.10516 · Cited by 32
Sharifzad, F., Yasavoli‐Sharahi, H., Mardpour, S., Fakharian, E., Nikuinejad, H., Heydari, Y., Mardpour, S., Taghikhani, A., khellat, R., Vafaei, S., et al. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28813 · Cited by 31
“Moreover, atypical activation of the P53 pathway is conducted to prevent apoptosis and cellular senescence, which promotes cancer progress (Kruse & Gu, 2009; Stracquadanio et al., 2016).”
BackgroundFibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma
Kelly, R. A., Perkumas, K. M., Campbell, M., Farrar, G. J., Stamer, W. D., Humphries, P., O’Callaghan, J., & O'Brien, C. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179446 · Cited by 32
“However, it is well documented that p53 regulation can occur at the post-translational level [54]; thus, analysis of p53 protein modifications and other cell cycle genes, such as Cyclin-A2 (CCNA2) and p16, could be the focus of future studies to provide insight on this mechanism.”
BackgroundYu, Y., Song, X., Ma, G., Zheng, L., Wang, X., Chen, F., Liu, T., Tian, H., Xu, Y., Li, D., et al. (2023) · Aging Cell · doi:10.1111/acel.13812 · Cited by 33
“…histone 2AX; H2O2, hydrogen peroxide; MG132, carbobenzoxy– Leu– Leu– leucinal; mRNA, messenger ribonucleic acid; Nur77, nuclear hormone receptor 77; p53, tumor protein p53; Sirt1, sirtuin 1 protein; MG132, Z– Leu– Leu– Leu– al; WCL, whole cell lysate. p53 for activation (Kruse & Gu, 2009).”
Modeling Lung Cancer Evolution and Preclinical Response by Orthotopic Mouse Allografts
Ambrogio, C., Carmona, F. J., Vidal, A., Falcone, M., Nieto, P., Romero, O. A., Puertas, S., Vizoso, M., Nadal, E., Poggio, T., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1606 · Cited by 32
“p53 is known to be stabilized in response to DNA damage and other stress signals, resulting in the induction of several downstream targets that mediate a variety of cellular responses such as cell-cycle arrest or apoptosis (16).”
BackgroundEmerging roles of p53 in glial cell function in health and disease
Jebelli, J. D., Hooper, C., Garden, G. A., & Pocock, J. M. (2011) · Glia · doi:10.1002/glia.22268 · Cited by 33
“The p53 protein regulates crucial and multifaceted functions in cell-cycle control, apoptosis, and the maintenance of genetic stability (Kruse and Gu, 2009).”
Jin, H., Liang, L., Liu, L., Deng, W., & Liu, J. (2013) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24491 · Cited by 32
“Post-translational modification of p53 has critical effects on its stability and function, including phosphorylation, acetylation, sumoylation, neddylation, and methylation [Kruse and Gu, 2009].”
BackgroundInflammatory cells regulate p53 and caspases in acute pancreatitis
Nakamura, Y., Do, J. H., Yuan, J., Odinokova, I. V., Mareninova, O. A., Gukovskaya, A. S., & Pandol, S. J. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00324.2009 · Cited by 32
Senescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke
Ouvrier, B., Ismael, S., & Bix, G. J. (2024) · Pharmaceuticals · doi:10.3390/ph17030312 · Cited by 32
“This activation is also dependent on several modifying factors, including phosphorylation, ubiquitination, neddylation, sumolyation, methylation, and acetylation [5,18].”
BackgroundFunctions of the native NPM1 protein and its leukemic mutant
Falini, B., Sorcini, D., Perriello, V. M., & Sportoletti, P. (2024) · Leukemia · doi:10.1038/s41375-024-02476-4 · Cited by 36
“…and NPM1 form a dimer in the nucleolus, allowing MDM2 to target p53 causing its nuclear export (following monoubiquitinylation) and proteasomal degradation (following polyubiquitinylation), and/or inhibition of its transactivation domain [89 – 91], which allows to maintain the p53 levels low.”
The role of acetylation and deacetylation in cancer metabolism
Wang, C., & Ma, X. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70145 · Cited by 32
UBTD1 induces cellular senescence through an UBTD1 –Mdm2/p53 positive feedback loop
Zhang, X.-W., Wang, X., Ni, S.-J., Qin, W., Zhao, L.-Q., Hua, R., Lu, Y.-W., Li, J., Dimri, G. P., & Guo, W. (2014) · The Journal of Pathology · doi:10.1002/path.4478 · Cited by 36
“Mdm2/Hdm2 is a well-known negative regulator of p53 [15,16], which controls p53 levels by targeting it for ubiquitin-mediated proteasomal degradation [17,18].”
BackgroundMathematical modelling of p53 basal dynamics and DNA damage response
Chong, K. H., Samarasinghe, S., & Kulasiri, D. (2014) · Mathematical Biosciences · doi:10.1016/j.mbs.2014.10.010 · Cited by 30
Novel HIV-1 therapeutics through targeting altered host cell pathways
Coley, W., Kehn‐Hall, K., Duyne, R. V., & Kashanchi, F. (2009) · Expert Opinion on Biological Therapy · doi:10.1517/14712590903257781 · Cited by 31
“p53 has been shown to be phosphorylated, acetylated, methylated, ubiquitinated, sumoylated, glycosylated, ADP-ribosylated and neddylated [38,39].”
Ogaly, H. A., Eltablawy, N. A., & Abd‐Elsalam, R. M. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/4039753 · Cited by 31
“In normal redox state, p53 expression and degradation are tightly regulated by a variety of proteins to maintain a low level of p53 [73].”
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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