Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
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.
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?
Loss of Mdm2 causes apoptosis and embryonic lethality at the blastocyst stage, and this phenotype is fully rescued by deleting p53 at the same time.
“Loss of Mdm2 leads to cell death by apoptosis and embryonic lethality at the blastocyst stage, and this phenotype is completely rescued by concomitant deletion of p53 (Chavez-Reyes, et al., 2003; Jones, et al., 1995; Montes de Oca Luna, et al., 1995).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Jones, et al., 1995
Cites
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 · see citing works
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 · see citing works
Self-citationParticipation 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 · 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
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 · 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
The Atlas of Mouse Development
Kaufman, M. H. (1992) · Medical Entomology and Zoology · Cited by 1,749 · see citing works
Mansour, S. L., Thomas, K. R., & Capecchi, M. R. (1988) · Nature · doi:10.1038/336348a0 · Cited by 1,683 · see citing works
The atlas of mouse development
Beddington, R. S. P. (1993) · Trends in Genetics · doi:10.1016/0168-9525(93)90071-o · Cited by 1,431 · see citing works
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 890 · see citing works
Self-citationp53 Functions as a Cell Cycle Control Protein in Osteosarcomas
Diller, L., Kassel, J., Nelson, C. E., Gryka, M. A., Litwak, G., Gebhardt, M. C., Bressac, B., Öztürk, M., Baker, S. J., Vogelstein, B., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.11.5772 · Cited by 775 · 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
Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein.Preprint
Martinez, J., Georgoff, I., Martinez, J., & Levine, A. J. (1991) · Genes & Development · doi:10.1101/gad.5.2.151 · Cited by 528 · see citing works
Mercer, W. E., Shields, M. T., Amin, M., Sauvé, G. J., Appella, E., Romano, J., & Ullrich, S. J. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.16.6166 · Cited by 477 · see citing works
CAHILLY, L. A., Yang‐Feng, T. L., Francke, U., & George, D. L. (1987) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01535205 · Cited by 355 · see citing works
Juven‐Gershon, T., Barak, Y., Zauberman, A., George, D. L., & Oren, M. (1993) · PubMed · Cited by 332 · see citing works
[51] Gene targeting in embryonic stem cells
Ramírez‐Solis, R., Davis, A. C., & Bradley, A. (1993) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(93)25054-6 · Cited by 327 · see citing works
Self-citationThe mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth.
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301 · Cited by 311 · see citing works
The human MDM-2 oncogene is overexpressed in leukemias
Bueso-Ramos, C., Yang, Y. S., deLeon, E., McCown, P., Stass, S. A., & Albitar, M. X. (1993) · Blood · doi:10.1182/blood.v82.9.2617.bloodjournal8292617 · Cited by 294 · see citing works
Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.
Chen, C. Y., Oliner, J., Zhan, Q., Fornace, A. J., Vogelstein, B., & Kastan, M. B. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.7.2684 · Cited by 271 · see citing works
Expression of p53 during mouse embryogenesis
Schmid, P., Lorenz, A., Hameister, H., & Montenarh, M. (1991) · Development · doi:10.1242/dev.113.3.857 · Cited by 246 · see citing works
Guide to techniques in mouse development
Wassarman, P. M., & Depamphilis, M. (1993) · Cited by 220 · see citing works
Regulation of Transcription Functions of the p53 Tumor Suppressor by the mdm-2 Oncogene
Chen, J., Lin, J., & Levine, A. J. (1995) · Molecular Medicine · doi:10.1007/bf03401562 · Cited by 214 · see citing works
Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes.
Olson, D. C., Maréchal, V., Momand, J. A., Chen, J., Romocki, C., & Levine, A. J. (1993) · PubMed · Cited by 188 · see citing works
Flagged first, then by citations
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).
Cited by
Sorted by citations
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
Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398 · see citing works
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
Self-citationLive 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
“cgi?l=4194">MDMX (MDM4) — have crucial roles in regulating p53 activity to allow normal growth and developmen”
Backgroundp53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
“5 of gestation (Jones et al. 1995; Montes de Oca Luna et al. 1995).”
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
The p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967 · see citing works
“Consistent with this interpretation is the observation that a p53, MDM-2 double knockout mouse is viable and is born as normal as a p53 knockout mouse (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
BackgroundMalignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316 · see citing works
“…cell line, and then later found to be a key negative regulator of p53 during normal development and in tumorigenesis (Fakharzadeh et al. 1991; Momand et al. 1992; Oliner et al. 1993; Jones et al. 1995; Montes de Oca Luna et al. 1995; Honda et al. 1997; Fang et al. 2000; Honda and Yasuda 2000).”
BackgroundComparative Genomics of the Eukaryotes
Rubin, G. M., Yandell, M. D., Wortman, J. R., Gabor, G. L., Miklos, Nelson, C. R., Hariharan, I. K., Fortini, M. E., Li, P. W., Apweiler, R., et al. (2000) · Science · doi:10.1126/science.287.5461.2204 · Cited by 1,698 · see citing works
Self-citationKruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610 · see citing works
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626 · see citing works
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 · see citing works
How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.169 · Cited by 1,395 · 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
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 · see citing works
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 · see citing works
“Mdm2 −/− mice are embryonic lethal, and deletion of both Trp53 alleles rescues this phenotyp”
BackgroundGain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
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 · see citing works
Oncogenic roles of EMT-inducing transcription factors
Puisieux, A., Brabletz, T., & Caramel, J. (2014) · Nature Cell Biology · doi:10.1038/ncb2976 · Cited by 1,032 · see citing works
p53 Activation by Knockdown Technologies
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 1,018 · see citing works
“Mdm2 knockout in mice is an embryonic lethal [13] due to extensive p53 upregulation and p53induced apoptosis.”
Backgroundp53 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 980 · see citing works
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 · see citing works
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 · see citing works
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
“5 of development (Montes de Oca Luna et al., 1995; Jones et al., 1995).”
BackgroundInfluentialAwakening 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 · see citing works
“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 · see citing works
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 · see citing works
“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).”
BackgroundInvolvement 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 · see citing works
Self-citationMoll, U. M., & Petrenko, O. (2003) · PubMed · Cited by 778 · see citing works
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
Chène, P. (2003) · Nature Reviews Cancer · doi:10.1038/nrc991 · Cited by 765 · see citing works
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 759 · see citing works
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 · see citing works
“…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.”
MethodPirh2, 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 717 · see citing works
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 · see citing works
“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.”
BackgroundA 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 · see citing works
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 · see citing works
p53 polymorphisms: cancer implications
Whibley, C., Pharoah, P. D. P., & Hollstein, M. C. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2584 · Cited by 667 · see citing works
“Although a complete lack of MDM2 in Mdm2 −/− mice is embryonic letha”
BackgroundMDMX: 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
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 · see citing works
Shangary, S., & Wang, S. (2009) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094723 · Cited by 623 · see citing works
“The physiological relevance of the MDM2-p53 loop has been demonstrated by the genetic evidence that embryonic lethality of MDM2-null mice can be rescued by the simultaneous deletion of the p53 gene (39,40).”
BackgroundRegulation 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 · see citing works
“…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).”
BackgroundRoth, 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 · see citing works
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
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 600 · see citing works
“Uncontrolled high levels of p53 in embryos lacking Mdm2 expression are detrimental to the developing embryo (Jones et al., 1995).”
BackgroundGeneration 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 · 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
“…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…”
BackgroundFunctions 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 · see citing works
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 · see citing works
“Cysteine 462 (464 in human) has been pretion of the p53 gene (Jones et al., 1995; Luna et al., 1995).”
BackgroundRescuing the function of mutant p53
Bullock, A. N., & Fersht, A. R. (2001) · Nature reviews. Cancer · doi:10.1038/35094077 · Cited by 565 · see citing works
Regulation of the p53 Tumor Suppressor Protein
Oren, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.51.36031 · Cited by 561 · see citing works
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 · see citing works
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 · see citing works
“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 539 · see citing works
Ludwig, T. E., Chapman, D. L., Papaioannou, V. E., & Efstratiadis, A. (1997) · Genes & Development · doi:10.1101/gad.11.10.1226 · Cited by 539 · 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
“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).”
BackgroundParant, 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
“This interaction is critical for cell viability; loss of Mdm2 causes cell death in vitro and in vivo in a p53-dependent manne”
BackgroundOncogenes and Tumor Suppressor GenesPreprint
Lee, E. Y., & Muller, W. J. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003236 · Cited by 515 · see citing works
“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).”
BackgroundUnderstanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 519 · see citing works
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 · see citing works
“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).”
Backgroundp63 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 482 · see citing works
“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).”
BackgroundPosttranslational Modification of p53: Cooperative Integrators of FunctionPreprint
Meek, D. W., & Anderson, C. W. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000950 · Cited by 487 · see citing works
“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).”
BackgroundInfluentialp53 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 481 · see citing works
Myc pathways provoking cell suicide and cancer
Nilsson, J. A., & Cleveland, J. L. (2003) · Oncogene · doi:10.1038/sj.onc.1207261 · Cited by 462 · see citing works
“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).”
BackgroundO-GlcNAc signalling: implications for cancer cell biology
Slawson, C. M., & Hart, G. W. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3114 · Cited by 459 · see citing works
“Owing to the pivotal role of p53 in maintaining genomic integrity, p53 is tightly regulated by proteolytic degradatio”
BackgroundZhao, Y., Aguilar, A., Bernard, D., & Wang, S. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501092z · Cited by 462 · see citing works
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 · see citing works
Self-citationAladjem, 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 442 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 423 · see citing works
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 · see citing works
p53-Dependent apoptosis pathways
Shen, Y., & White, E. (2001) · Advances in cancer research · doi:10.1016/s0065-230x(01)82002-9 · Cited by 415 · see citing works
Lipkowitz, S., & Weissman, A. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3120 · Cited by 415 · see citing works
“The relationship between MDM2 and p53 was established by early embryonic lethality in Mdm2 −/− mice and their rescue by crossing with Trp53 −/− mic”
BackgroundAshcroft, M. A., & Vousden, K. H. (1999) · Oncogene · doi:10.1038/sj.onc.1203012 · Cited by 407 · see citing works
“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).”
BackgroundFunctional 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 · see citing works
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 398 · see citing works
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 · see citing works
“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.”
BackgroundInfluentialTwo faces of p53: aging and tumor suppression
Rodier, F., Campisi, J., & Bhaumik, D. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm744 · Cited by 399 · see citing works
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 · see citing works
“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).”
BackgroundInfluentialOverexpression 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 · see citing works
Self-citationMultiple 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 · see citing works
“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).”
BackgroundIwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Langheinrich, U., Hennen, E., Stott, G. M., & Vacun, G. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01319-2 · Cited by 368 · see citing works
Brady, C. A., & Attardi, L. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.064501 · Cited by 374 · see citing works
“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).”
BackgroundTargeting 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 364 · see citing works
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 · see citing works
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 · 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
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 · see citing works
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 356 · see citing works
“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).”
BackgroundStress 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 356 · see citing works
“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).”
Backgroundp53-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 355 · see citing works
“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).”
BackgroundKeeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352 · see citing works
Efstratiadis, A. (1998) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9853827 · Cited by 349 · see citing works
“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.”
- 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
- Published
- 1995-11
- Volume
- 378
- Issue
- 6553
- Pages
- 206-208
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
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
