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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.
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“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
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BackgroundCell type‐specific inhibition of p53‐mediated apoptosis by mdm2.
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“The importance of MDM2 in p53 control is highlighted by the finding thatMdm2 knockout results in p53-dependent embryonic lethality in mice (2, 3).”
BackgroundRegulation of Mdm2-Directed Degradation by the C Terminus of p53
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mdmx is a negative regulator of p53 activity in vivo.
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E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2.
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Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3
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“The importance of Mdm2, the mouse isoform of Hdm2, in regulating p53 is shown by the embryonic lethality of mdm2 deletion (7, 8), which is specific for the loss of Mdm2-mediated p53 inhibition as deletion of both p53 and mdm2 results in viable animals that have an increased frequency of tumors similar to those with p5…”
BackgroundComparative study of the p53-mdm2 and p53-MDMX interfaces
Böttger, V., Böttger, A., Garcia-Echeverria, C., Ramos, Y. F., van der Eb, A. J., Jochemsen, A. G., & Lane, D. P. (1999) · Oncogene · doi:10.1038/sj.onc.1202281 · Cited by 189
“MDMX can obviously not compensate for lack of mdm2 function during early stages of embryonic development as mdm2 knockout experiments suggest (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
BackgroundKrummel, K. A., Lee, C. J., Toledo, F., & Wahl, G. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503068102 · Cited by 187
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 189
Brooks, C. L., & Gu, W. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.022 · Cited by 186
“Interestingly, the lethality is completely rescued in a double knockout of mdm2 and p53 [9–12].”
BackgroundChibaya, L., Karim, B. O., Zhang, H., & Jones, S. N. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003193118 · Cited by 191
Self-citationBiological and clinical importance of the p53 tumor suppressor gene
Velculescu, V. E., & El‐Deiry, W. S. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.6.858 · Cited by 175
Inactivation of HAUSP in vivo modulates p53 function.
Kon, N., Kobayashi, Y., Li, M., Brooks, C. L., Ludwig, T., & Gu, W. (2010) · Oncogene · doi:10.1038/onc.2009.427 · Cited by 176
“However, combining a p53-null background with the mdm2 knockout rescues this phenotype, suggesting that Mdm2 is a major negative regulator of p53 (Jones et al., 1995; Montes de Oca Luna et al., 1995).”
Regulating the p53 system through ubiquitination
Yang, Y., Li, C.-C. H., & Weissman, A. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207411 · Cited by 184
Targeting Apoptosis Pathways for New Cancer Therapeutics
Bai, L., & Wang, S. (2013) · Annual Review of Medicine · doi:10.1146/annurev-med-010713-141310 · Cited by 179
Ribosomal protein S14 unties the MDM2–p53 loop upon ribosomal stress
Zhou, X. Y., Hao, Q., Liao, J., Zhang, Q., & Lu, H. (2012) · Oncogene · doi:10.1038/onc.2012.63 · Cited by 176
Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies
Micel, L. N., Tentler, J. J., Smith, P. G., & Eckhardt, G. S. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.0958 · Cited by 178
p53-Mediated Repression of Alpha-Fetoprotein Gene Expression by Specific DNA Binding
Lee, K. C., Crowe, A. J., & Barton, M. C. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.2.1279 · Cited by 175
p53 Activation by Small Molecules: Application in Oncology
Vassilev, L. T. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058174k · Cited by 174
The role of p53-target genes in human cancer
Tokino, T., & Nakamura, Y. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(99)00051-7 · Cited by 179
Phan, J., Li, Z., Kasprzak, A., Li, B., Sebti, S., Guida, W., Schönbrunn, E., & Chen, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.073056 · Cited by 173
Wu, L., & Levine, A. J. (1997) · Molecular Medicine · doi:10.1007/bf03401691 · Cited by 172
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
“Human U2OS and HEK293 cells, and p53/mdm2 double knock-out (DKO) MEFs (Jones et al, 1995) were cultured at 371C/5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum, 2mM L-glutamine, 50U/ml penicillin G and 50mg/ml streptomycin sulfate.”
MethodGenotoxic and non-genotoxic pathways of p53 induction
Pluquet, O., & Hainaut, P. L. (2001) · Cancer Letters · doi:10.1016/s0304-3835(01)00698-x · Cited by 177
The Transactivation Domains of the p53 ProteinPreprint
Raj, N., & Attardi, L. D. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026047 · Cited by 178
Sung, T., Miller, D. C., Hayes, R. L., Alonso, M., Yee, H. T., & Newcomb, E. W. (2000) · Brain Pathology · doi:10.1111/j.1750-3639.2000.tb00258.x · Cited by 167
Momand, J. A., & Zambetti, G. P. (1997) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19970301)64:3 · Cited by 167
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168
ATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
Meulmeester, E., Pereg, Y., Shiloh, Y., & Jochemsen, A. G. (2005) · Cell Cycle · doi:10.4161/cc.4.9.1981 · Cited by 173
Metadata
- 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
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