Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo
Open accessAbstract
The Mdm2 and Mdm4 oncoproteins are key negative regulators of the p53 tumor suppressor. However, their physiological contributions to the regulation of p53 stability and activity remain highly controversial. Here, we combined a p53 knock-in allele, in which p53 is silenced by a transcriptional stop element flanked by loxP sites, with the mdm2 - and mdm4 -null alleles. This approach allows Cre-mediated conditional p53 expression in tissues in vivo and cells in vitro lacking Mdm2, Mdm4, or both. Using this strategy, we show that Mdm2 and Mdm4 are essential in a nonredundant manner for preventing p53 activity in the same cell type, irrespective of the proliferation/differentiation status of the cells. Although Mdm2 prevents accumulation of the p53 protein, Mdm4 contributes to the overall inhibition of p53 activity independent of Mdm2. We propose a model in which Mdm2 is critical for the regulation of p53 levels and Mdm4 is critical for the fine-tuning of p53 transcriptional activity, both proteins acting synergistically to keep p53 in check.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mdm4 directly interacts with p53 to disrupt its DNA-binding and transcriptional activation.
“Further, Mdm4 directly interacts with p53 to disrupts its DNA-binding and transcriptional activation (Francoz et al., 2006; Wei et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Francoz et al., 2006
Mdm2 and Mdmx contribute to p53 regulation to different extents in different tissues in vivo.
“Mdm2 and Mdmx seem to contribute to p53 regulation to different extents in different tissues in vivo (Table 1; [32–40]).”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [33]
In some tissues and cell types, such as the central nervous system and proliferative intestinal cells, there is a requirement for both Mdm2 and Mdmx.
“Clearly in some tissues and cell types [such as the central nervous system (CNS) and proliferative intestinal cells], there is a requirement for both Mdm2 and Mdmx.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [33]
In smooth muscle cells, loss of Mdmx has no phenotype.
“However, in other cases, such as smooth muscle cells, loss of Mdmx has no phenotype.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [33]
Proliferating cells are more sensitive than resting cells to MDM2 and MDMX depletion.
“Proliferating cells are more sensitive than resting cells to MDM2 and MDMX depletion24.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [24]
Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo and that they exert non-overlapping inhibitory activities towards p53.
“Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108 and that they exert non-overlapping inhibitory activities towards p53 (Refs 24,109).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [24]
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 Francoz et al, 2006
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · see citing works
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety
Tronche, F., Kellendonk, C., Kretz, O., Gass, P., Anlag, K., Orban, P. C., Bock, R., Klein, R., & Schütz, G. (1999) · Nature Genetics · doi:10.1038/12703 · Cited by 1,841 · see citing works
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801 · see citing works
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · see citing works
mdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · see citing works
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · see citing works
Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2
Li, M., Brooks, C. L., Wu-Baer, F., Chen, D., Baer, R., & Gu, W. (2003) · Science · doi:10.1126/science.1091362 · Cited by 804 · see citing works
Mapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 689 · see citing works
Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis.Preprint
Lowe, S. W., & Ruley, H. E. (1993) · Genes & Development · doi:10.1101/gad.7.4.535 · Cited by 662 · see citing works
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells
Loonstra, A., Vooijs, M., Beverloo, H. B., Allak, B. A., van Drunen, E., Kanaar, R., Berns, A. J. M., & Jonkers, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161269798 · Cited by 591 · see citing works
Graus-Porta, D., Blaess, S., Senften, M., Littlewood-Evans, A., Damsky, C. H., Huang, Z., Orban, P. C., Klein, R., Schittny, J. C., & Müller, U. (2001) · Neuron · doi:10.1016/s0896-6273(01)00374-9 · Cited by 559 · see citing works
Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G. (2001) · Nature Genetics · doi:10.1038/ng714 · Cited by 517 · see citing works
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
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
Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids
Schmidt, E. E., Taylor, D., Prigge, J. R., Barnett, S., & Capecchi, M. R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.240471297 · Cited by 335 · see citing works
Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P. G., & Marine, J.-C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5527-5538.2002 · Cited by 313 · see citing works
Self-citationStabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286 · see citing works
Schwab, M. H., Bartholomä, A., Heimrich, B., Feldmeyer, D., Druffel‐Augustin, S., Goebbels, S., Naya, F. J., Zhao, S., Frotscher, M., Tsai, M., et al. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-10-03714.2000 · Cited by 258 · see citing works
Mapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107-4114.1993 · Cited by 247 · see citing works
Mendrysa, S. M., McElwee, M. K., Michalowski, J., O'Leary, K. A., Young, K. M., & Perry, M. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.2.462-473.2003 · Cited by 234 · see citing works
Mdmx as an essential regulator of p53 activity
Marine, J., & Jochemsen, A. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.151 · Cited by 186 · see citing works
Self-citationSynergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Liu, G., & Lozano, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508500103 · Cited by 155 · see citing works
Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
Grier, J. D., Xiong, S., Elizondo-Fraire, A. C., Parant, J. M., & Lozano, G. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.192-198.2006 · Cited by 149 · see citing works
Death squads enlisted by the tumour suppressor p53
Michalak, E. M., Villunger, A., Erlacher, M., & Strasser, A. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.183 · Cited by 114 · see citing works
Conditional allele of mdm2 which encodes a p53 inhibitor
Grier, J. D., Yan, W., & Lozano, G. (2002) · genesis · doi:10.1002/gene.10066 · Cited by 57 · see citing works
MDM2 expression during mouse embryogenesis and the requirement of p53
Léveillard, T., Gorry, P., Niederreither, K., & Wasylyk, B. (1998) · Mechanisms of Development · doi:10.1016/s0925-4773(98)00074-4 · Cited by 41 · see citing works
G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv
Doumont, G., Martoriati, A., Beekman, C., Bogaerts, S., Mee, P. J., Bureau, F., Colombo, E., Alcalay, M., Bellefroid, E., Marchesi, F., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600769 · Cited by 38 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
Signaling 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
MDM2 inhibitors for cancer therapy
Vassilev, L. T. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.11.002 · Cited by 532 · see citing works
Coping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
The 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
Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
Self-citationClinical Overview of MDM2/X-Targeted Therapies
Burgess, A., Chia, K. M., Haupt, S., Thomas, D., Haupt, Y., & Lim, E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00007 · Cited by 315 · see citing works
The 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
MDM2 and MDM4: p53 regulators as targets in anticancer therapy
Toledo, F., & Wahl, G. M. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.03.022 · Cited by 261 · see citing works
Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo
Ringshausen, I., O'Shea, C. C., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.010 · Cited by 256 · see citing works
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Carvajal, L. A., Neriah, D. B., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., Narayanagari, S.-R., Wheat, J. C., Todorova, T. I., Mitchell, K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao3003 · Cited by 249 · see citing works
Itahana, K., Mao, H., Jin, A., Itahana, Y., Clegg, H. V., Lindström, M. S., Bhat, K. P., Godfrey, V. L., Evan, G. I., & Zhang, Y. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.09.007 · Cited by 245 · see citing works
MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin
Hu, B., Gilkes, D. M., Farooqi, B., Sebti, S. M., & Chen, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c600147200 · Cited by 236 · see citing works
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
Self-citationToledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · see citing works
Brooks, C. L., & Gu, W. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.022 · Cited by 186 · see citing works
An essential function of the extreme C-terminus of MDM2 can be provided by MDMX
Uldrijan, S., Pannekoek, W., & Vousden, K. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601469 · Cited by 170 · see citing works
Hdmx modulates the outcome of p53 activation in human tumor cells
Wade, M., Wong, E. T., Tang, M., Stommel, J. M., & Wahl, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605405200 · Cited by 163 · see citing works
ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
Cheng, Q., Chen, L., Li, Z., Lane, W. S., & Chen, J. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.294 · Cited by 165 · 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
Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53
Kostic, M., Matt, T., Martinez-Yamout, M. A., Dyson, H. J., & Wright, P. E. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.08.027 · Cited by 128 · see citing works
USP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
“Further, Mdm4 directly interacts with p53 to disrupts its DNA-binding and transcriptional activation (Francoz et al., 2006; Wei et al., 2016).”
BackgroundCellular and molecular mechanisms of sarcopenia: The S100B perspective
Riuzzi, F., Sorci, G., Arcuri, C., Giambanco, I., Bellezza, I., Minelli, A., & Donato, R. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12363 · Cited by 114 · 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
Differential 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
Roles of HAUSP-mediated p53 regulation in central nervous system development
Kon, N., Zhong, J., Kobayashi, Y., Li, M., Szabolcs, M., Ludwig, T., Canoll, P. D., & Gu, W. (2011) · Cell Death & Differentiation · doi:10.1038/cdd.2011.12 · Cited by 79 · see citing works
Validation of MdmX as a therapeutic target for reactivating p53 in tumors
Garcia, D., Warr, M. R., Martins, C. P., Brown Swigart, L., Passegué, E., & Evan, G. I. (2011) · Genes & Development · doi:10.1101/gad.16722111 · Cited by 83 · see citing works
Loss of <i>Mdm4</i> Results in <i>p53</i> -Dependent Dilated Cardiomyopathy
Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Fernandez-Garcia, B., & Lozano, G. (2007) · Circulation · doi:10.1161/circulationaha.107.689901 · Cited by 71 · see citing works
Boesten, L. S. M., Zadelaar, S. M., De Clercq, S., Francoz, S., van Nieuwkoop, A., Biessen, E. A. L., Hofmann, F., Feil, S., Feil, R., Jochemsen, A. G., et al. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401973 · Cited by 70 · see citing works
Self-citationDistinct roles of Mdm2 and Mdm4 in red cell production
Maetens, M., Doumont, G., Clercq, S. D., Francoz, S., Froment, P., Bellefroid, E., Klingmuller, U., Lozano, G., & Marine, J.-C. (2007) · Blood · doi:10.1182/blood-2006-03-013656 · Cited by 64 · see citing works
Self-citationThe intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival
Valentin-Vega, Y. A., Okano, H., & Lozano, G. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.109 · Cited by 58 · see citing works
Matijasevic, Z., Steinman, H. A., Hoover, K., & Jones, S. N. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01108-07 · Cited by 58 · see citing works
Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding.
Wei, X., Wu, S., Song, T., Chen, L., Gao, M., Borcherds, W., Daughdrill, G. W., & Chen, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603838113 · Cited by 50 · see citing works
Structural and Functional Comparison of the RING Domains of Two p53 E3 Ligases, Mdm2 and Pirh2
Shloush, J., Vlassov, J. E., Engson, I., Duan, S., Saridakis, V., Dhe-paganon, S., Raught, B., Sheng, Y., & Arrowsmith, C. H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.157669 · Cited by 42 · see citing works
De Clercq, S., Gembarska, A., Denecker, G., Maetens, M., Naessens, M., Haigh, K., Haigh, J. J., & Marine, J.-C. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00330-10 · Cited by 35 · see citing works
Self-citationMdmX 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
Valentin-Vega, Y. A., Box, N., Terzian, T., & Lozano, G. (2009) · Differentiation · doi:10.1016/j.diff.2009.03.001 · Cited by 28 · see citing works
- Authors
- Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., & Marine, J.-C.
- Affiliations
- Université Libre de Bruxelles (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-21
- Volume
- 103
- Issue
- 9
- Pages
- 3232-3237
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1413884
- OpenAlex
- W1994169350
- Cited by
- 260
- References
- 34
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 14 · 2016: 14 · 2015: 6 · 2014: 16 · 2013: 16 · 2012: 21
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Massachusetts Institute of Technology
- European Commission
- 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
- MDM2, MDM4, p53, p53 regulation, p53 stabilization, p53 transcriptional activity, knockout mice, cell proliferation, quiescent cells, tumor suppressor
- MeSH terms
- Animals, Fibroblasts, Neurons, Proto-Oncogene Proteins, Stem Cells, Tumor Suppressor Protein p53, Mice, Knockout, Gene Expression Regulation, Developmental, Ubiquitin-Protein Ligases, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
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 ›
Are you an author, or do you see a problem with this page? Request a review
