Cited by 1,280Cancer-related Molecular PathwaysDevelopmental Biology and Gene RegulationCell death mechanisms and regulation

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Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53

Jones, Stephen N., Roe, Amy E., Donehower, Lawrence A., Bradley, Allan·1995·Nature

DOI 10.1038/378206a0

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Abstract

The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells. Overexpression of Mdm2 can immortalize primary cultures of rodent fibroblasts. Human MDM2 is amplified in 30-40% of sarcomas, and is overexpressed in leukaemic cells. The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53-mediated transregulation of gene expression. Because Mdm2 expression increases in response to p53, Mdm2-p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell. We have created Mdm2-null and Mdm2/p53-null mice to determine whether Mdm2 possesses developmental functions in addition to the ability to complex with p53, and to investigate the biological role of Mdm2-p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 and p53 develop normally and are viable. These results suggest that a critical role of Mdm2 in development is the regulation of p53 function.

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p53 Mutations in Human Cancers
Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991) · Science · doi:10.1126/science.1905840 · Cited by 8,018
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Butel, J. S., & Bradley, A. (1992) · Nature · doi:10.1038/356215a0 · Cited by 4,649
Self-citation
Participation of p53 protein in the cellular response to DNA damage.
Kastan, M. B., Onyekwere, O. C., Sidransky, D., Vogelstein, B., & Craig, R. W. (1991) · PubMed · Cited by 3,761
The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation
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
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949
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
The Atlas of Mouse Development
Kaufman, M. H. (1992) · Medical Entomology and Zoology · Cited by 1,750
Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes
Mansour, S. L., Thomas, K. R., & Capecchi, M. R. (1988) · Nature · doi:10.1038/336348a0 · Cited by 1,683
The atlas of mouse development
Beddington, R. S. P. (1993) · Trends in Genetics · doi:10.1016/0168-9525(93)90071-o · Cited by 1,416
α-lnhibin is a tumour-suppressor gene with gonadal specificity in mice
Matzuk, M. M., Finegold, M. J., Su, J.-G. J., Hsueh, A. J. W., & Bradley, A. (1992) · Nature · doi:10.1038/360313a0 · Cited by 893
Self-citation

Show all 24 references

Research works printed but not linked: 5

Juven, T., Barak, Y., Zauberman, A., George, D. & Oren, M. Oncogene 8, 3411–3416 (1993).
Snow, M. H. L. J. Embryol. exp. Morph. 42, 293–303 (1977).
Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. V. & Vogelstein, B. Science 253, 49–53 (1990).
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Cancer Res. 51, 6304–6311 (1991).
Olson, D. C. et al. Oncogene 8, 2353–2360 (1993).

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Background
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Background
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Self-citation
Modes of p53 regulation.
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
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Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81400-2 · Cited by 1,521
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Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
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Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.022 · Cited by 1,265
When mutants gain new powers: News from the mutant p53 field
Brosh, R., & Rotter, V. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2693 · Cited by 1,132
“Mdm2 −/− mice are embryonic lethal, and deletion of both Trp53 alleles rescues this phenotyp”
Background
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Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.006 · Cited by 1,069
Oncogenic roles of EMT-inducing transcription factors
Puisieux, A., Brabletz, T., & Caramel, J. (2014) · Nature Cell Biology · doi:10.1038/ncb2976 · Cited by 1,073
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Robu, M. E., Larson, J. D., Nasevicius, A., Beiraghi, S., Brenner, C., Farber, S. A., & Ekker, S. C. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0030078 · Cited by 1,049
“Mdm2 knockout in mice is an embryonic lethal [13] due to extensive p53 upregulation and p53induced apoptosis.”
Background
p53 and Human Cancer: The First Ten Thousand Mutations
Hainaut, P. L., & Hollstein, M. C. (1999) · Advances in cancer research · doi:10.1016/s0065-230x(08)60785-x · Cited by 999
Nucleolar Arf sequesters Mdm2 and activates p53
Weber, J. D., Taylor, L. J., Roussel, M. F., Sherr, C. J., & Bar-Sagi, D. (1999) · Nature Cell Biology · doi:10.1038/8991 · Cited by 940
The development of the concept of ferroptosis
Hirschhorn, T., & Stockwell, B. R. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.043 · Cited by 1,052
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924
“5 of development (Montes de Oca Luna et al., 1995; Jones et al., 1995).”
BackgroundInfluential
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
“Therefore, Trp53 −/− Mdm2 −/− mice are viable, whereas Trp53 +/− Mdm2 −/− results in embryonic lethality; this is also the case for Mdm4 −/− mic”
Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2
Kamijo, T., Weber, J. D., Zambetti, G., Zindy, F., Roussel, M. F., & Sherr, C. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8292 · Cited by 899
Acetylation Is Indispensable for p53 Activation
Tang, Y., Zhao, W., Chen, Y., Zhao, Y., & Gu, W. (2008) · Cell · doi:10.1016/j.cell.2008.03.025 · Cited by 838
“The central role of Mdm2 in this process is best illustrated by studies carried out in mice where inactivation of p53 was shown to completely rescue the embryonic lethality caused by loss of Mdm2 function (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over
Baker, S. M., Plug, A. W., Prolla, T. A., Bronner, C. E., Harris, A. C., Yao, X., Christie, D. M., Monell, C. R., Arnheim, N., Bradley, A., et al. (1996) · Nature Genetics · doi:10.1038/ng0796-336 · Cited by 821
Self-citation
The MDM2-p53 interaction.
Moll, U. M., & Petrenko, O. (2003) · PubMed · Cited by 778
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
Chène, P. (2003) · Nature Reviews Cancer · doi:10.1038/nrc991 · Cited by 765
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 772
A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking
Stommel, J. M., Marchenko, N. D., Jimenez, G. S., Moll, U. M., Hope, T. J., & Wahl, G. M. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1660 · Cited by 738
“…were maintained in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS). p53–/–/ mdm2–/– mouse embryonic fibroblasts [kindly provided by Drs Allan Bradley and Stephen Jones (Jones et al., 1995)], were maintained in DMEM with 10% dialyzed FBS and non-essential amino acids.”
Method
Pirh2, a p53-Induced Ubiquitin-Protein Ligase, Promotes p53 Degradation
Leng, R. P., Lin, Y., Ma, W., Wu, H., Lemmers, B., Chung, S., Parant, J. M., Lozano, G., Hakem, R., & Benchimol, S. (2003) · Cell · doi:10.1016/s0092-8674(03)00193-4 · Cited by 731
The complexity of p53 stabilization and activation
Lavin, M. F., & Gueven, N. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401925 · Cited by 701
“In addition, knockout of MDM2 in mice is embryonic lethal and when combined in a double knockout with p53 this phenotype is rescued suggesting that no back-up p53 ubiquitin ligase is operational during development.(53) MDM2 is a proto-oncogene amplified in a significant number of tumours.”
Background
A dynamic role of HAUSP in the p53-Mdm2 pathway
Li, M., Brooks, C. L., Kon, N., & Gu, W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00157-1 · Cited by 679
The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.
Hakem, R., de la Pompa, J. L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81302-1 · Cited by 680
p53 polymorphisms: cancer implications
Whibley, C., Pharoah, P. D. P., & Hollstein, M. C. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2584 · Cited by 677
“Although a complete lack of MDM2 in Mdm2 −/− mice is embryonic letha”
Background
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
MDM2 — master regulator of the p53 tumor suppressor protein
Momand, J., Wu, H.-H., & Dasgupta, G. (2000) · Gene · doi:10.1016/s0378-1119(99)00487-4 · Cited by 641
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Shangary, S., & Wang, S. (2009) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094723 · Cited by 623
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Background
Regulation of HDM2 activity by the ribosomal protein L11
Lohrum, M. A. E., Ludwig, R. L., Kubbutat, M. H. G., Hanlon, M., & Vousden, K. H. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00134-x · Cited by 626
“…Mdm2 results in early embryonic lethality that is the consequence of p53-mediated apoptosis (de Rozieres et al., 2000;that around half of all human cancers have lost p53 activity through mutation within the p53 gene, while many others show Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Nucleo‐cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein
Roth, J., Dobbelstein, M., Freedman, D. A., Shenk, T., & Levine, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.554 · Cited by 610
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 625
The cellular response to p53: the decision between life and death
Sionov, R. V., & Haupt, Y. (1999) · Oncogene · doi:10.1038/sj.onc.1203130 · Cited by 608
“Uncontrolled high levels of p53 in embryos lacking Mdm2 expression are detrimental to the developing embryo (Jones et al., 1995).”
Background
Generation of oscillations by the p53-Mdm2 feedback loop: A theoretical and experimental study
Bar‐Or, R. L., Maya, R. B.-Y., Segel, L. A., Alon, U., Levine, A. J., & Oren, M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.210171597 · Cited by 579
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Zhang, Y., & Lu, H. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.024 · Cited by 591
“…a transcriptional target of p53 (Barak et al., 1993; Wu et al., 1993) and deletion of Tp53 completely rescues the lethality of Mdm2 knockout mice (Jones et al., 1995; Montes de Oca Luna et al., 1995), the primary physiological function of MDM2 is thus to serve as a negative feedback ‘‘knot’’ for…”
Background
Functions of the MDM2 oncoprotein
Freedman, D. A., Wu, L., & Levine, A. J. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050273 · Cited by 573
Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity
Xirodimas, D. P., Saville, M. K., Bourdon, J.-C., Hay, R. T., & Lane, D. P. (2004) · Cell · doi:10.1016/j.cell.2004.06.016 · Cited by 570
“Cysteine 462 (464 in human) has been pretion of the p53 gene (Jones et al., 1995; Luna et al., 1995).”
Background
Rescuing the function of mutant p53
Bullock, A. N., & Fersht, A. R. (2001) · Nature reviews. Cancer · doi:10.1038/35094077 · Cited by 579
Regulation of the p53 Tumor Suppressor Protein
Oren, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.51.36031 · Cited by 567
p73: Friend or foe in tumorigenesis
Melino, G., Laurenzi, V. D., & Vousden, K. H. (2002) · Nature reviews. Cancer · doi:10.1038/nrc861 · Cited by 554
Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway
Zhang, Y., Wolf, G. W., Bhat, K., Jin, A., Allio, T., Burkhart, W., & Xiong, Y. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.23.8902-8912.2003 · Cited by 556
“target of MDM2 during development (16, 22).”
ARF-BP1/Mule Is a Critical Mediator of the ARF Tumor Suppressor
Chen, D., Kon, N., Li, M., Zhang, W., Qin, J., & Gu, W. J. (2005) · Cell · doi:10.1016/j.cell.2005.03.037 · Cited by 551
Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos.Preprint
Ludwig, T. E., Chapman, D. L., Papaioannou, V. E., & Efstratiadis, A. (1997) · Genes & Development · doi:10.1101/gad.11.10.1226 · Cited by 539
MDM2 inhibitors for cancer therapy
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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
“By far the best studied of these is Mdm2 (sometimes referred to as HDM2 in humans) – a RING finger protein that is essential to regulate p53 and allow survival during normal development (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53
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
“This interaction is critical for cell viability; loss of Mdm2 causes cell death in vitro and in vivo in a p53-dependent manne”
Background
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 575
“Deletion of TP53 rescues embryonic lethality in Mdm2- and Mdm4-deficient mice (Jones et al. 1995; Montes de Oca Luna et al. 1995; Parant et al. 2001).”
Background
Understanding 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 538
Ribosomal Protein L23 Activates p53 by Inhibiting MDM2 Function in Response to Ribosomal Perturbation but Not to Translation Inhibition
Dai, M., Zeng, S. X., Jin, Y., Sun, X., David, L. L., & Lu, H. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.17.7654-7668.2004 · Cited by 495
“Indeed, genetic disruption of the p53 gene rescues the lethal phenotype of the mdm2 knockout mouse, firmly validating the notion of the MDM2-p53 feedback loop (27, 43).”
Background
p63 and p73: Roles in Development and Tumor Formation
Moll, U. M., & Slade, N. (2004) · Molecular Cancer Research · doi:10.1158/1541-7786.371.2.7 · Cited by 488
“p53 has an important developmental role in early mouse embryogenesis (E7-8d) as revealed when the autoregulatory feedback loop with MDM2 is removed and p53 levels remain uncontrolled (40, 41).”
Background
Posttranslational 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 510
“Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a000950 3 and in adult mice (Jones et al. 1995; Montes de Oca Luna et al. 1995; Ringshausen et al. 2006).”
BackgroundInfluential
p53 in growth control and neoplasia
Gottlieb, T. M., & Oren, M. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00019-c · Cited by 483
Myc pathways provoking cell suicide and cancer
Nilsson, J. A., & Cleveland, J. L. (2003) · Oncogene · doi:10.1038/sj.onc.1207261 · Cited by 470
“The net result of disrupting Mdm2 functions is p53 accumulation, activation and then cell death, a concept underscored by the Mdm2 knockout mouse, which dies early during embryonic development, unless crossed onto a p53-deficient background (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment
Zhao, Y., Aguilar, A., Bernard, D., & Wang, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501092z · Cited by 462
O-GlcNAc signalling: implications for cancer cell biology
Slawson, C. M., & Hart, G. W. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3114 · Cited by 466
“Owing to the pivotal role of p53 in maintaining genomic integrity, p53 is tightly regulated by proteolytic degradatio”
Background
Retention of wild‐type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation
Venkatachalam, S., Shi, Y., Jones, S. N., Vogel, H. S., Bradley, A., Pinkel, D., & Donehower, L. A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.16.4657 · Cited by 449
Self-citation
ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage
Aladjem, M. I., Spike, B. T., Rodewald, L. W., Hope, T. J., Klemm, M., Jaenisch, R., & Wahl, G. M. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70061-2 · Cited by 453
CDC5 and CKII Control Adaptation to the Yeast DNA Damage Checkpoint
Toczyski, D. P., Galgoczy, D. J., & Hartwell, L. H. (1997) · Cell · doi:10.1016/s0092-8674(00)80375-x · Cited by 431
Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation
Connor, F., Bertwistle, D., Mee, P. J., Ross, G. M., Swift, S., Grigorieva, E. F., Tybulewicz, V. L. J., & Ashworth, A. (1997) · Nature Genetics · doi:10.1038/ng1297-423 · Cited by 432
A complex barcode underlies the heterogeneous response of p53 to stress
Murray-Zmijewski, F., Slee, E. A., & Lu, X. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2451 · Cited by 420
Yin Yang 1 Is a Negative Regulator of p53
Sui, G., Affar, E. B., Shi, Y. G., Brignone, C., Wall, N. R., Yin, P., Donohoe, M., Luke, M. P.-S., Calvo, D., Grossman, S. R., et al. (2004) · Cell · doi:10.1016/j.cell.2004.06.004 · Cited by 433
Advances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Henley, M. J., & Koehler, A. N. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00199-0 · Cited by 409
p53-Dependent apoptosis pathways
Shen, Y., & White, E. (2001) · Advances in cancer research · doi:10.1016/s0065-230x(01)82002-9 · Cited by 424
RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis
Lipkowitz, S., & Weissman, A. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3120 · Cited by 422
“The relationship between MDM2 and p53 was established by early embryonic lethality in Mdm2 −/− mice and their rescue by crossing with Trp53 −/− mic”
Background
Regulation of p53 stability
Ashcroft, M. A., & Vousden, K. H. (1999) · Oncogene · doi:10.1038/sj.onc.1203012 · Cited by 411
“The control that Mdm2 exerts over p53 is essential for normal development, since Mdm2 de®cient mice show a very early embryonic lethality (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Functional analysis of secreted and transmembrane proteins critical to mouse development.
Mitchell, K. J., Pinson, K. I., Kelly, O. G., Brennan, J., Zupicich, J., Scherz, P., Leighton, P. A., Goodrich, L. V., Lu, X., Avery, B. J., et al. (2001) · Nature Genetics · doi:10.1038/90074 · Cited by 400
The role of mutant p53 in human cancer
Goh, A. M., Coffill, C. R., & Lane, D. P. (2010) · The Journal of Pathology · doi:10.1002/path.2784 · Cited by 408
Mcl-1 deficiency results in peri-implantation embryonic lethality
Rinkenberger, J. L., Horning, S., Klocke, B., Roth, K., & Korsmeyer, S. J. (2000) · Genes & Development · doi:10.1101/gad.14.1.23 · Cited by 397
“However, the introduction of p53 deficiency did not rescue the Mcl-1 nulls as it had for Mdm2 (Jones et al. 1995; Montes de Oca Luna et al. 1995) and rad51 (Lim and Hasty 1996) nor did the introduction of Bax deficiency (Knudson et al.”
BackgroundInfluential
Two faces of p53: aging and tumor suppression
Rodier, F., Campisi, J., & Bhaumik, D. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm744 · Cited by 412
Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Stommel, J. M., & Wahl, G. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600145 · Cited by 386
“The importance of MDM2 in p53 regulation is evidenced by the embryonic lethality of MDM2 knockout mice, presumably due to unrestrained p53 activity (Jones et al, 1995; Montes de Oca Luna et al, 1995).”
BackgroundInfluential
Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis
Jones, S. N., Hancock, A. R., Vogel, H., Donehower, L. A., & Bradley, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15608 · Cited by 386
Self-citation
Multiple C-Terminal Lysine Residues Target p53 for Ubiquitin-Proteasome-Mediated Degradation
Rodríguez, M. S., Desterro, J. M. P., Laı́n, S., Lane, D. P., & Hay, R. T. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.22.8458-8467.2000 · Cited by 386
“The importance of this regulatory mechanism is illustrated by the fact that deletion of the mdm2 gene in mice induces an early embryonic lethality which is rescued by deletion of the p53 gene (24).”
Background
MDM2, an introduction.
Iwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381
Disruption of HAUSP gene stabilizes p53.
Cummins, J. M., Rago, C., Kohli, M., Kinzler, K. W., Lengauer, C., & Vogelstein, B. (2004) · Nature · doi:10.1038/nature02501 · Cited by 379
Mutation of E2f-1 Suppresses Apoptosis and Inappropriate S Phase Entry and Extends Survival of Rb-Deficient Mouse Embryos
Tsai, K. Y., Hu, Y., Macleod, K. F., Crowley, D., Yamasaki, L., & Jacks, T. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80274-9 · Cited by 372
Zebrafish as a Model Organism for the Identification and Characterization of Drugs and Genes Affecting p53 Signaling
Langheinrich, U., Hennen, E., Stott, G. M., & Vacun, G. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01319-2 · Cited by 373
p53 at a glance
Brady, C. A., & Attardi, L. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.064501 · Cited by 400
“The crucial importance of MDM2 in regulating p53 was demonstrated using Mdm2-null mice, which display very early embryonic lethality (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Background
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 372
Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2
Unger, T., Juven‐Gershon, T., Moallem, E., Berger, M., Sionov, R. V., Lozano, G., Oren, M., & Haupt, Y. (1999) · The EMBO Journal · doi:10.1093/emboj/18.7.1805 · Cited by 365
Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Böttger, A., Böttger, V., Sparks, A., Liu, W.-L., Howard, S. F., & Lane, D. P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00374-5 · Cited by 363
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354
Opposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357
The inherent instability of mutant p53 is alleviated by Mdm2 or p16 INK4a lossPreprint
Terzian, T., Suh, Y., Iwakuma, T., Post, S. M., Neumann, M., Lang, G. A., Pelt, C. S. V., & Lozano, G. (2008) · Genes & Development · doi:10.1101/gad.1662908 · Cited by 363
“Mdm2-null mice are embryonic lethal due to stabilization of p53 and massive apoptosis, a phenotype that is rescued by loss of p53 (Jones et al. 1995; Montes de Oca Luna et al. 1995; Chavez-Reyes et al. 2003).”
Background
Stress Signals Utilize Multiple Pathways To Stabilize p53
Ashcroft, M. A., Taya, Y., & Vousden, K. H. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.9.3224-3233.2000 · Cited by 360
“The importance of regulation of p53 by MDM2 during normal development is dramatically illustrated by the complete rescue of the early embryonic lethality of MDM2deficient mice by simultaneous deletion of p53 (24, 35).”
Background
p53-independent functions of the p19ARF tumor suppressorPreprint
Weber, J. D., Jeffers, J. R., Rehg, J. E., Randle, D. H., Lozano, G., Roussel, M. F., Sherr, C. J., & Zambetti, G. P. (2000) · Genes & Development · doi:10.1101/gad.827300 · Cited by 361
“Disruption of Mdm2 leads to embryonic lethality, which is rescued on a p53-null background (Jones et al. 1995; Montes de Oca Luna et al. 1995).”
Background
Genetics of mouse growth
Efstratiadis, A. (1998) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9853827 · Cited by 357
“This happens, for example, in nullizygous Os mutants (oligosyndactylism; see Pravtecheva and Wise, 1996, and other references therein) and in knockouts of the genes Mdm2 (Jones et al., 1995; Montes de Oca Luna et al., 1995), Ccna2 (cyclin A2; Murphy et al.”
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

Authors: Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A.
Affiliations: Howard Hughes Medical Institute (US)
Baylor College of Medicine (US)
ORCID: Bradley, Allan
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1995-11
Volume: 378
Issue: 6553
Pages: 206-208
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/378206a0
OpenAlex: W1993864973
Semantic Scholar: efc84bf5f5d1747443a3eb4555f9b5ede31b368f
Cited by: 1,280
References: 24
Citations by year: 2026: 9 · 2025: 17 · 2024: 30 · 2023: 31 · 2022: 28 · 2021: 35 · 2020: 41 · 2019: 28 · 2018: 31 · 2017: 38 · 2016: 54 · 2015: 34 · 2014: 59 · 2013: 30 · 2012: 60
FWCI: 14.50
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: MDM2, p53, embryonic lethality, developmental regulation, tumor suppressor, sarcoma, leukemia
MeSH terms: Proto-Oncogene Mas, Animals, Base Sequence, Cell Cycle, Cell Line, Crosses, Genetic, Female, Embryonic and Fetal Development, Genes, Lethal, Molecular Sequence Data, Mutation, Nuclear Proteins, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, 3T3 Cells, DNA Primers, Gene Targeting, Mice, Proto-Oncogene Proteins c-mdm2

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Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53

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