A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network
Open accessAbstract
The mechanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53DeltaP). p53DeltaP exhibited increased sensitivity to Mdm2-dependent degradation and decreased transactivation capacity, correlating with deficient cell cycle arrest and reduced apoptotic responses. p53DeltaP induced lethality in Mdm2-/- embryos, but not in Mdm4-/- embryos. Mdm4 loss did not alter Mdm2 stability but significantly increased p53DeltaP transactivation to partially restore cycle control. In contrast, decreasing Mdm2 levels increased p53DeltaP levels without altering p53DeltaP transactivation. Thus, Mdm4 regulates p53 activity, while Mdm2 mainly controls p53 stability. Furthermore, Mdm4 loss dramatically improved p53DeltaP-mediated suppression of oncogene-induced tumors, emphasizing the importance of targeting Mdm4 in chemotherapies designed to activate p53.
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MDMX regulates p53 mainly by forming inactive p53-MDMX complexes.
“it seems to regulate p53 mainly by formation of inactive p53-MDMX complexes (Francoz et al, 2006;Toledo et al, 2006).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Toledo et al, 2006
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ResultSmalley, K. S. M., Contractor, R., Haass, N. K., Kulp, A. N., Atilla‐Gokcumen, G. E., Williams, D. S., Bregman, H. S., Flaherty, K. T., Soengas, M. S., Meggers, E., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-1538 · Cited by 229 · see citing works
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“Analyses of p53 P regulation by Mdm2 and Mdmx produced similar results (Toledo et al., 2006). p53 interacts with the p300 histone acetyltransferase and this interaction appears to be essential for p53-dependent activation of the promoter of the p53-target gene p21 (Liu et al., 2003). p53 itself is…”
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BackgroundMethodInfluentialIdentification and Characterization of the First Small Molecule Inhibitor of MDMX
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“The peptides representing the isolatedAD1 andAD2 subdomains bind approximately 170- and 8-fold more weakly than p53(1-61), respectively.”
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Self-citationATM activates p53 by regulating MDM2 oligomerization and E3 processivity
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“However, MDMX does not have significant intrinsic E3 ligase activity (Stad et al, 2001), it seems to regulate p53 mainly by formation of inactive p53–MDMX complexes (Francoz et al, 2006; Toledo et al, 2006).”
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
Ganesh, S. K., Tragante, V., Guo, W., Guo, Y., Lanktree, M. B., Smith, E. N., Johnson, T., Castillo, B. A., Barnard, J., Baumert, J. J., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds555 · Cited by 148 · see citing works
MDMX regulation of p53 response to ribosomal stress
Gilkes, D. M., Chen, L., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601424 · Cited by 142 · see citing works
“In contrast, MDMX is a stable protein that regulates p53 mainly by sequestering p53 into complexes (Francoz et al, 2006; Toledo et al, 2006).”
BackgroundCooperation between the ribosomal proteins L5 and L11 in the p53 pathway
Horn, H. F., & Vousden, K. H. (2008) · Oncogene · doi:10.1038/onc.2008.189 · Cited by 140 · see citing works
“, 1997), the critical function of MDM2 is as a ubiquitin ligase, regulating p53 stability by promoting its ubiquitination and subsequent degradation (Haupt et al., 1997; Honda et al., 1997; Kubbutat et al., 1997; Toledo et al., 2006; Itahana et al., 2007).”
BackgroundOne, two, three—p53, p63, p73 and chemosensitivity
MULLER, M., Schleithoff, E. S., Stremmel, W., Melino, G., Krammer, P. H., & Schilling, T. (2006) · Drug Resistance Updates · doi:10.1016/j.drup.2007.01.001 · Cited by 140 · see citing works
Reactivation of p53: from peptides to small molecules
Brown, C. J., Cheok, C. F., Verma, C. S., & Lane, D. P. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.11.004 · Cited by 135 · see citing works
Molecular Basis for the Inhibition of p53 by Mdmx
Popowicz, G. M., Czarna, A., Rothweiler, U., Szwagierczak, A., Krajewski, M., Weber, L., & Holak, T. A. (2007) · Cell Cycle · doi:10.4161/cc.6.19.4740 · Cited by 131 · see citing works
Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Müller, C. R., Paulsen, E. B., Noordhuis, P., Pedeutour, F., Sæter, G., & Myklebost, O. (2007) · International Journal of Cancer · doi:10.1002/ijc.22643 · Cited by 119 · see citing works
Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701497104 · Cited by 116 · see citing works
Self-citationp53 downstream target genes and tumor suppression: a classical view in evolution
Rozan, L. M., & El‐Deiry, W. S. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402058 · Cited by 115 · see citing works
MdmX is a substrate for the deubiquitinating enzyme USP2a
Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K. (2010) · Oncogene · doi:10.1038/onc.2009.330 · Cited by 100 · see citing works
Melatonin down‐regulates MDM 2 gene expression and enhances p53 acetylation in MCF ‐7 cells
Proietti, S., Cucina, A., Dobrowolny, G., D’Anselmi, F., Dinicola, S., Masiello, M. G., Pasqualato, A., Palombo, A., Morini, V., Reiter, R. J., et al. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12150 · Cited by 96 · see citing works
“Yet, our results are supported by previous reports demonstrating that MDMX loss leads to a moderate increase in MDM2 levels, without appreciably affecting p53 activity [39].”
ResultDifferential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage
Pereg, Y., Lam, S., Teunisse, A., Biton, S., Meulmeester, E., Mittelman, L., Buscemi, G., Okamoto, K., Taya, Y., Shiloh, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00562-06 · Cited by 93 · see citing works
“These reports proposed a model in which Mdm2 serves to mainly regulate p53 stability and Mdmx functions as a major inhibitor of p53 transcriptional activity (16, 29, 58, 64).”
BackgroundInteraction between p53 N terminus and core domain regulates specific and nonspecific DNA binding
He, F., Borcherds, W. M., Song, T., Wei, X., Das, M., Chen, L., Daughdrill, G. W., & Chen, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903077116 · Cited by 95 · see citing works
Yurube, T., Hirata, H., Kakutani, K., Maeno, K., Takada, T., Zhang, Z., Takayama, K., Matsushita, T., Kuroda, R., Kurosaka, M., et al. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4460 · Cited by 95 · see citing works
“DNA damage phosphorylates p53 by dissociation of the complex of p53 and its negative regulators, murine double minutes 2 and 4 [15].”
BackgroundThe Regulation of the p53-mediated Stress Response by MDM2 and MDM4Preprint
Perry, M. E. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000968 · Cited by 92 · see citing works
“On a biochemical level, MDM2 deletion results in accumulation of p53 and a concomitant increase in p53dependent transactivation, whereas MDM4 deletion results in increased p53-dependent transactivation without p53 stabilization (Francoz et al. 2006; Toledo et al. 2006).”
BackgroundPelay‐Gimeno, M., Glas, A., Koch, O., & Grossmann, T. N. (2015) · Angewandte Chemie · doi:10.1002/ange.201412070 · Cited by 90 · see citing works
MicroRNA-34a Modulates MDM4 Expression via a Target Site in the Open Reading Frame
Mandke, P., Wyatt, N., Fraser, J., Bates, B., Berberich, S. J., & Markey, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042034 · Cited by 90 · see citing works
“certain tumor types, such as colon cancer [2], gliomas [3–5] and retinoblastomas [6].”
BackgroundIn vivo analysis of p53 tumor suppressor function using genetically engineered mouse models
Brož, D. K., & Attardi, L. D. (2010) · Carcinogenesis · doi:10.1093/carcin/bgp331 · Cited by 89 · see citing works
The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases
Anbarasan, T., & Bourdon, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246257 · Cited by 81 · see citing works
Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes
Simeonova, I., Jaber, S., Drašković, I., Bardot, B., Fang, M., Bouarich-Bourimi, R., Lejour, V., Charbonnier, L., Soudais, C., Bourdon, J., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.05.028 · Cited by 85 · see citing works
Self-citationMDMX (MDM4), a Promising Target for p53 Reactivation Therapy and BeyondPreprint
Marine, J., & Jochemsen, A. G. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026237 · Cited by 81 · see citing works
“Important insights into Mdmx function also came from the analysis of the hypomorphic p53 mouse model, in which Mdmx-deficiency can be fully rescued (Toledo et al. 2006).”
BackgroundMutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice
Li, Y. R., Halliwill, K. D., Adams, C., Iyer, V., Riva, L., Mamunur, R., Jen, K., Rosario, R. D., Fredlund, E., Hirst, G. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14261-4 · Cited by 77 · see citing works
Mancini, F., Conza, G. D., Pellegrino, M., Rinaldo, C., Prodosmo, A., Giglio, S., D’Agnano, I., Florenzano, F., Felicioni, L., Buttitta, F., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.154 · Cited by 81 · see citing works
Peptidomimetics: A Synthetic Tool for Inhibiting Protein–Protein Interactions in Cancer
Mabonga, L., & Kappo, A. P. (2019) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-019-09831-5 · Cited by 78 · see citing works
Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase
Okamoto, K., Taya, Y., & Nakagama, H. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.07.021 · Cited by 76 · see citing works
“Because Mdmx does not significantly contribute to p53 degradation [34], we attempted to determine whether Mdmx stimulates mono-ubiquitination of p53 rather than its poly-ubiquitination.”
Backgroundp53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo
Timofeev, O. N., Schlereth, K., Wanzel, M., Braun, A., Nieswandt, B., Pagenstecher, A., Rosenwald, A., Elsässer, H., & Stiewe, T. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.008 · Cited by 76 · see citing works
“Conversely, a mutant of p53 in the proline-rich region, which is deficient in cell-cycle arrest functions but retains proapoptotic activity, reduces spontaneous tumorigenesis in genemodified mice (Toledo et al., 2006).”
BackgroundMeek, D. W., & Hupp, T. R. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.10.005 · Cited by 76 · see citing works
Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform
Slatter, T. L., Hung, N. A., Campbell, H. G., Rubio, C., Mehta, R., Renshaw, P., Williams, G., Wilson, M., Engelmann, A., Jeffs, A. R., et al. (2011) · Blood · doi:10.1182/blood-2010-11-321851 · Cited by 72 · see citing works
β-Peptides with improved affinity for hDM2 and hDMX
Harker, E. A., Daniels, D. S., Guarracino, D. A., & Schepartz, A. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.01.039 · Cited by 71 · see citing works
Inhibition of p53 DNA Binding Function by the MDM2 Protein Acidic Domain
Cross, B. L., Chen, L., Cheng, Q., Li, B., Yuan, Z.-M., & Chen, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228981 · Cited by 69 · see citing works
Singh, R. K., Iyappan, S., & Scheffner, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610879200 · Cited by 69 · see citing works
Holstege, H. H., Horlings, H. M., Velds, A., Langerød, A., Børresen‐Dale, A., van de Vijver, M. J., Nederlof, P. M., & Jonkers, J. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-654 · Cited by 63 · see citing works
“The peak of the chromosome 1q gain of the luminal tumor group maps to 202.75 Mb, with the MDM4 gene at (202.81 Mb), which is a negative regulator of p53 [ 48 ].”
InfluentialToledo, F., Lee, C. J., Krummel, K. A., Rodewald, L.-W., Liu, C.-W., & Wahl, G. M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00999-06 · Cited by 64 · see citing works
“We used homologous recombination to introduce the desired mutations into the endogenous Trp53 locus as described previously (28).”
BackgroundMethodResultInfluentialSelf-citationCrippling p53 activities via knock-in mutations in mouse models
Iwakuma, T., & Lozano, G. (2007) · Oncogene · doi:10.1038/sj.onc.1210278 · Cited by 63 · see citing works
“Moreover, mice with a small p53 deletion that retains only a partial apoptotic response also exhibit delayed tumor onset suggesting that both activities of p53 are important in in vivo tumor suppression (Toledo et al., 2006).”
BackgroundEnsemble-based virtual screening reveals dual-inhibitors for the p53–MDM2/MDMX interactions
Barakat, K., Mane, J. Y., Friesen, D. E., & Tuszyński, J. A. (2009) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2009.12.003 · Cited by 61 · see citing works
“Although MDMX lacks the intrinsic E3 ligase activity of MDM2 [13], current models suggest that it functions as a major p53 transcriptional antagonist independent of MDM2 [14].”
MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output
Chen, L., Li, Z., Zwolińska, A., Smith, M. A., Cross, B. L., Koomen, J. M., Yuan, Z.-M., Jenuwein, T., Marine, J., Wright, K. L., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.140 · Cited by 61 · see citing works
“Recent studies suggest that the major mechanism of p53 regulation by MDMX is the formation of transcriptionally inactive p53–MDMX complexes, whereas MDM2 primary functions to regulate p53 turnover (Francoz et al, 2006; Toledo et al, 2006).”
BackgroundTP53-independent Function of miR-34a via HDAC1 and p21CIP1/WAF1
Zhao, J. Y., Lammers, P., Torrance, C. J., & Bader, A. G. (2013) · Molecular Therapy · doi:10.1038/mt.2013.148 · Cited by 59 · see citing works
Illuminating p53 function in cancer with genetically engineered mouse models
Garcia, P. B., & Attardi, L. D. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.12.014 · Cited by 59 · see citing works
Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 57 · see citing works
p53 as an intervention target for cancer and aging
Hasty, P., & Christy, B. A. (2013) · Pathobiology of Aging & Age-related Diseases · doi:10.3402/pba.v3i0.22702 · Cited by 56 · see citing works
“Furthermore, MDM2 appears to regulate p53 stability whereas MDM4 regulates p53 activity (54).”
BackgroundToufektchan, E., Lejour, V., Durand, R., Giri, N., Drašković, I., Bardot, B., Laplante, P., Jaber, S., Alter, B. P., Londoño‐Vallejo, A., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay3511 · Cited by 50 · see citing works
“This is reminiscent of what was previously observed in another mouse model, in which Mdm4 loss was found to increase p53 activity, but decrease p53 stability (53).”
Self-citationDeacetylation of p53 induces autophagy by suppressing Bmf expression
Contreras, A. U., Mebratu, Y., Delgado, M., Montano, G., Hu, C.-A. A., Ryter, S. W., Choi, A. M. K., Lin, Y., Xiang, J., Chand, H., et al. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201205064 · Cited by 48 · see citing works
“In mice, this PRD consists of two PXXP motifs, and we obtained mice with a deletion of the PRD (p53P) or lacking the four critical proline residues at loci 79, 82, 84, and 87 that make up the tandem PXXP sites (p53AXXA; Toledo et al., 2006, 2007).”
The genotypes and phenotypes of missense mutations in the proline domain of the p53 protein
Hoyos, D., Greenbaum, B. D., & Levine, A. J. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00980-7 · Cited by 48 · see citing works
Anderson, C. W., & Appella, E. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00264-3 · Cited by 48 · see citing works
Genetic modeling of Li-Fraumeni syndrome in zebrafish
Parant, J. M., George, S. A., Holden, J. A., & Yost, H. J. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.003749 · Cited by 46 · see citing works
“…are remnants of functionality in mutant p53 proteins in multiple tissues and pathways, including apoptosis, cell cycle arrest, and others (Chavez-Reyes et al., 2003; Iwakuma et al., 2004; Jones et al., 1995; Lang et al., 2004; Liu et al., 2007; Montes de Oca Luna et al., 1995; Toledo et al., 2006).”
BackgroundMadan, E., Parker, T. M., Bauer, M. R., Dhiman, A., Pelham, C. J., Nagane, M., Kuppusamy, M. L., Holmes, M., Holmes, T. R., Shaik, K., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000950 · Cited by 45 · see citing works
“The P53 transcription factor regulates oncogenic progression via multiple mechanisms that involve, but are not restricted to, cell cycle arrest, senescence, and apoptosis (3-5).”
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 43 · see citing works
Golubovskaya, V., Finch, R., Zheng, M., Kurenova, E., & Cance, W. G. (2008) · Biochemical Journal · doi:10.1042/bj20071657 · Cited by 43 · see citing works
Spinnler, C., Hedström, E., Li, H., de Lange, J., Nikulenkov, F., Teunisse, A. F. A. S., Vries, M. V., Grinkevich, V. V., Jochemsen, A. G., & Selivanova, G. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.45 · Cited by 42 · see citing works
Guo, Y., Wu, H., Wiesmüller, L., & Chen, M. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06783-7 · Cited by 40 · see citing works
p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors
Slatter, T. L., Ganesan, P. L., Holzhauer, C., Mehta, R., Rubio‐Terres, C., Williams, G., Wilson, M., Royds, J. A., Baird, M. A., & Braithwaite, A. W. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.136 · Cited by 41 · see citing works
Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB
Hernández‐Monge, J., Rousset-Roman, A. B., Medina‐Medina, I., & Olivares‐Illana, V. (2016) · Genes & Cancer · doi:10.18632/genesandcancer.120 · Cited by 41 · see citing works
“Until a few years ago, MDM2 and MDMX were considered the main negative regulators of p53 [49, 84-88], but recent evidence supports the idea that they can switch to being positive regulators of p53 depending on the cellular conditions [8-11].”
BackgroundKrajewski, M., Rothweiler, U., D’Silva, L., Majumdar, S., Klein, C., & Holak, T. A. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm070365v · Cited by 40 · see citing works
Characterization of Functional Domains Necessary for Mutant p53 Gain of Function
Yan, W., & Chen, X. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.097253 · Cited by 40 · see citing works
MDM2 and MDMX in Cancer and Development
Marine, J. (2011) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-380916-2.00003-6 · Cited by 38 · see citing works
Switching on p53: an essential role for protein phosphorylation?
Loughery, J., & Meek, D. W. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.1 · Cited by 38 · see citing works
Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis
Benosman, S., Groß, I., Clarke, N., Jochemsen, A. G., Okamoto, K., Loeffler, J., & Gaiddon, C. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402216 · Cited by 38 · see citing works
“However, recent data obtained with different mouse models suggest that the main function of MDMX is to repress p53mediated transcription without having a major function in the regulation of p53 levels.(9,10) Some of these discrepancies may”
BackgroundBardot, B., Bouarich-Bourimi, R., Leemput, J., Lejour, V., Hamon, A., Plancke, L., Jochemsen, A. G., Simeonova, I., Fang, M., & Toledo, F. (2014) · Oncogene · doi:10.1038/onc.2014.230 · Cited by 41 · see citing works
Self-citationVu, T. T., Stölzel, F., Wang, K. W., Röllig, C., Tursky, M. L., Molloy, T. J., & Ma, D. D. F. (2020) · Leukemia · doi:10.1038/s41375-020-01095-z · Cited by 37 · see citing works
CARPs enhance p53 turnover by degrading 14-3-3σ and stabilizing MDM2
Yang, W., Dicker, D. T., Chen, J., & El‐Deiry, W. S. (2008) · Cell Cycle · doi:10.4161/cc.7.5.5701 · Cited by 36 · see citing works
Liao, X.-H., Zhang, Y., Dong, W.-J., Shao, Z., & Li, D.-Q. (2017) · OncoTarget · doi:10.18632/oncotarget.18556 · Cited by 37 · see citing works
“For instance, the PRD domain in tumor suppressor protein p53 contributes to the regulation of its protein stability and p53-mediate apoptosis and tumor suppression [54, 55, 64, 65].”
BackgroundThe 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 36 · see citing works
MdmX regulates transformation and chromosomal stability in p53-deficient cells
Matijasevic, Z., Krzywicka-Racka, A., Sluder, G., & Jones, S. N. (2008) · Cell Cycle · doi:10.4161/cc.7.19.6797 · Cited by 34 · see citing works
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2
Ohtsubo, C., Shiokawa, D., Kodama, M., Gaiddon, C., Nakagama, H., Jochemsen, A. G., Taya, Y., & Okamoto, K. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01180.x · Cited by 32 · see citing works
Wu, Z., Chen, D., Wang, K., Cao, C., & Xu, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01260 · Cited by 32 · see citing works
“Therefore,MDM4 can suppress the transactivation and apoptosis-causing function of p53 (23).”
BackgroundA Function for the RING Finger Domain in the Allosteric Control of MDM2 Conformation and Activity
Wawrzynów, B., Pettersson, S., Żylicz, M., Bramham, J., Worrall, E. G., Hupp, T. R., & Ball, K. L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809294200 · Cited by 32 · see citing works
Chand, H. S., Montano, G., Huang, X., Randell, S. H., Mebratu, Y. A., Petersen, H. V., & Tesfaigzi, Y. (2014) · Nature Communications · doi:10.1038/ncomms6567 · Cited by 32 · see citing works
Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses
Timofeev, O. N., Klimovich, B., Schneikert, J., Wanzel, M., Pavlakis, E., Noll, J., Mutlu, S., Elmshäuser, S., Nist, A., Mernberger, M., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2019102096 · Cited by 31 · see citing works
“…occurring mutations of post-translational modification sites (Sluss et al , 2004; Slee et al , 2010; Li et al , 2012) or functional domains (Toledo et al , 2006; Brady et al , 2011; Hamard et al , 2013; Simeonova et al , 2013) have yielded substantial mechanistic insight into the pathways…”
RMCE-ASAP: a gene targeting method for ES and somatic cells to accelerate phenotype analyses
Toledo, F. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl518 · Cited by 30 · see citing works
“tion ( 5 ). Likewise, we found that irradiation doses that arrested p53RMCE/� MEFs (which express a wild-type p53”
BackgroundMethodInfluentialSelf-citationDoes control of mutant p53 by Mdm2 complicate cancer therapy?: Figure 1.Preprint
Prives, C. L., & White, E. (2008) · Genes & Development · doi:10.1101/gad.1680508 · Cited by 30 · see citing works
Macchiarulo, A., Giacchè, N., Carotti, A., Baroni, M., Cruciani, G., & Pellicciari, R. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800146m · Cited by 29 · see citing works
- Authors
- Toledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Toledo, Franck
- Wahl, Geoffrey M.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 9
- Issue
- 4
- Pages
- 273-285
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2059985270
- Cited by
- 199
- References
- 56
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 14 · 2012: 13
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- U.S. Public Health Service (100845)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, MDM4, MDM2, proline-rich region, p53 stabilization, p53 transactivation, cell cycle arrest, apoptosis, tumor suppression, p53-targeted therapy, mouse mutants
- MeSH terms
- Animals, Cells, Cultured, DNA, DNA Damage, Mice, Transgenic, Mutation, Neoplasms, Proline, Proto-Oncogene Proteins, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Protein Structure, Tertiary, Ubiquitin-Protein Ligases, Mice, Proto-Oncogene Proteins c-mdm2
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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