MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein)
| Written | 2006-12 | Wenrui Duan, Miguel A Villalona-Calero |
| Comprehensive Cancer Center, 1230 JCHRI, 300 West 10th Ave, Columbus, Ohio 43210, USA |
(Note : for Links provided by Atlas : click)
1. Identity
| Alias_names | General Information |
| Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse) | |
| Mdm2 p53 binding protein homolog (mouse) | |
| MDM2 proto-oncogene, E3 ubiquitin protein ligase | |
| Alias_symbol (synonym) | HDM2 |
| MGC5370 | |
| Other alias | HDMX |
| hdm2 | |
| HGNC (Hugo) | MDM2 |
| LocusID (NCBI) | 4193 |
| Atlas_Id | 115 |
| Location | 12q15 [Link to chromosome band 12q15] |
| Location_base_pair | Starts at 68808172 and ends at 68845544 bp from pter ( according to hg19-Feb_2009) [Mapping MDM2.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| C12orf49 (12q24.22) / MDM2 (12q15) | CTDSP2 (12q14.1) / MDM2 (12q15) | FAM133B (7q21.2) / MDM2 (12q15) | |
| FRS2 (12q15) / MDM2 (12q15) | LRIG3 (12q14.1) / MDM2 (12q15) | MDM2 (12q15) / CCT3 (1q22) | |
| MDM2 (12q15) / COMMD2 (3q25.1) | MDM2 (12q15) / EGFR (7p11.2) | MDM2 (12q15) / NUP107 (12q15) | |
| MDM2 (12q15) / PPM1H (12q14.1) | MDM2 (12q15) / RINT1 (7q22.3) | MDM2 (12q15) / RUNX2 (6p21.1) | |
| MDM2 (12q15) / UBE2J2 (1p36.33) | MYRFL (12q15) / MDM2 (12q15) | PPM1H (12q14.1) / MDM2 (12q15) | |
| SBF2 (11p15.4) / MDM2 (12q15) | TRIM27 (6p22.1) / MDM2 (12q15) | UAP1 (1q23.3) / MDM2 (12q15) | |
| ZFC3H1 (12q21.1) / MDM2 (12q15) |
2. DNA/RNA
| Description | The gene encompasses 33 kb of DNA; 12 exons. |
| Transcription | 2.3 kb nucleotides mRNA. 1476 b open reading frame. |
3. Protein
| Description | 491 amino acids; 90 kDa protein. |
| Expression | Expression of MDM2 during embryogenesis was studied in mice. During 14.5 to 18.5 days of prenatal development, the nasal respiratory epithelium expresses high levels of MDM2 RNA and protein in both wild type and p53 null embryos. MDM2 expression during development is tissue-specific and is independent of p53. The mdm2 basal mRNA expression appears relatively moderate in most organs in adult mice. MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkin's lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL). |
| Localisation | MDM2 protein was found in nucleus and cytoplasm. |
| Function | MDM2 was originally cloned from transformed Balb/c3T3 cell line called 3T3DM and was identified as an amplified oncogene in murine cell lines. MDM2 was shown to be amplified in approximately 30% of osteosarcomas and soft tissue tumors and was subsequently found to act as an ubiquitin ligase promoting proteasome dependent degradation of p53. MDM2 is also a transcriptional target of p53 such that p53 activity controls the expression and protein level of its own negative regulator, providing for an elegant feedback loop. MDM2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. The MDM2-p53 complex also inhibits p53 mediated transactivation. MDM2 knockout mouse embryos died during development and deletion of the p53 gene rescues MDM2 null embryos. These studies suggested that p53 is lethal in the absence of MDM2 during mouse development and MDM2 is a critical regulator to control p53 activity. In addition, MDM2 involves nuclear export of p53 protein. Interaction between the p53 and MDM2 is not sufficient to mediate p53 degradation. The p53 MDM2 complex must be shuttled from the nucleus to the cytoplasm in order for p53 degradation. Besides, the MDM2 protein also promotes RB (retinoblastoma) protein degradation in a proteasome-dependent manner in human tumor cell lines. MDM2 overexpression contributes to cancer development in part by destabilizing RB. Interaction between MDM2 and the tumor suppressor genes p53 and Rb lead to deregulate cell proliferation and apoptosis. MDM2 is a key factor in human tumorigenesis. Both MDM2 and Pirh2 (RCHY1) proteins are p53 ubiquitin-protein E3 ligases promoting for degradation of p53 protein. However, MDM2 operates in a distinct manner from Pirh2 in response to DNA damage in cancer cells. MDM2 protein is reduced or absent in the p53 null cells compared to the p53 positive cells, Whereas, Pirh2 expression is not affected by the status of p53. A single nucleotide polymorphism (SNP309) found in the MDM2 promoter is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. |
| Homology | The MDM2 gene has been identified in various organisms including mammals, amphibians and fishes. It belongs to the ring finger ubiquitin protein E3 ligase family, containing Conserved RING-finger Domain. |
4. Mutations
| Note | MDM2 mutations are uncommon. Point mutations were reported in human cancers. |
5. Implicated in
| Note | |
| Entity | Soft tissue tumors and osteosarcomas. |
| Disease | A set of data of MDM2 amplification based on 3889 samples from tumors or xenografts from 28 tumor types from previously published sources was collected. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). |
| Oncogenesis | MDM2 is amplified in many cancers. Because the MDM2 is an ubiquitin-protein ligase that promotes p53 protein degradation, the increased MDM2 protein could play an important role in tumorigenesis, especially in the development of soft tissue tumors, osteosarcomas and esophageal carcinomas. |
6. Bibliography
| mdm2 expression is induced by wild type p53 activity. |
| Barak Y, Juven T, Haffner R, Oren M |
| The EMBO journal. 1993 ; 12 (2) : 461-468. |
| PMID 8440237 |
| A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. |
| Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ |
| Cell. 2004 ; 119 (5) : 591-602. |
| PMID 15550242 |
| Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. |
| Cahilly-Snyder L, Yang-Feng T, Francke U, George DL |
| Somatic cell and molecular genetics. 1987 ; 13 (3) : 235-244. |
| PMID 3474784 |
| Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. |
| Chen CY, Oliner JD, Zhan Q, Fornace AJ Jr, Vogelstein B, Kastan MB |
| Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (7) : 2684-2688. |
| PMID 8146175 |
| mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. |
| Chen J, Wu X, Lin J, Levine AJ |
| Molecular and cellular biology. 1996 ; 16 (5) : 2445-2452. |
| PMID 8628312 |
| Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells. |
| Duan W, Gao L, Wu X, Zhang Y, Otterson GA, Villalona-Calero MA |
| Experimental cell research. 2006 ; 312 (17) : 3370-3378. |
| PMID 16934800 |
| Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. |
| Fakharzadeh SS, Trusko SP, George DL |
| The EMBO journal. 1991 ; 10 (6) : 1565-1569. |
| PMID 2026149 |
| Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. |
| Freedman DA, Levine AJ |
| Molecular and cellular biology. 1998 ; 18 (12) : 7288-7293. |
| PMID 9819415 |
| Mdm2 promotes the rapid degradation of p53. |
| Haupt Y, Maya R, Kazaz A, Oren M |
| Nature. 1997 ; 387 (6630) : 296-299. |
| PMID 9153395 |
| Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. |
| Honda R, Tanaka H, Yasuda H |
| FEBS letters. 1997 ; 420 (1) : 25-27. |
| PMID 9450543 |
| Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. |
| Jones SN, Roe AE, Donehower LA, Bradley A |
| Nature. 1995 ; 378 (6553) : 206-208. |
| PMID 7477327 |
| Regulation of p53 stability by Mdm2. |
| Kubbutat MH, Jones SN, Vousden KH |
| Nature. 1997 ; 387 (6630) : 299-303. |
| PMID 9153396 |
| MDM2 expression during mouse embryogenesis and the requirement of p53. |
| Léveillard T, Gorry P, Niederreither K, Wasylyk B |
| Mechanisms of development. 1998 ; 74 (1-2) : 189-193. |
| PMID 9651526 |
| The MDM2 gene amplification database. |
| Momand J, Jung D, Wilczynski S, Niland J |
| Nucleic acids research. 1998 ; 26 (15) : 3453-3459. |
| PMID 9671804 |
| The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. |
| Momand J, Zambetti GP, Olson DC, George D, Levine AJ |
| Cell. 1992 ; 69 (7) : 1237-1245. |
| PMID 1535557 |
| Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. |
| Montes de Oca Luna R, Wagner DS, Lozano G |
| Nature. 1995 ; 378 (6553) : 203-206. |
| PMID 7477326 |
| Amplification of a gene encoding a p53-associated protein in human sarcomas. |
| Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B |
| Nature. 1992 ; 358 (6381) : 80-83. |
| PMID 1614537 |
| Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. |
| Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B |
| Nature. 1993 ; 362 (6423) : 857-860. |
| PMID 8479525 |
| The mdm-2 gene is induced in response to UV light in a p53-dependent manner. |
| Perry ME, Piette J, Zawadzki JA, Harvey D, Levine AJ |
| Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (24) : 11623-11627. |
| PMID 8265599 |
| Point mutations and nucleotide insertions in the MDM2 zinc finger structure of human tumours. |
| Schlott T, Reimer S, Jahns A, Ohlenbusch A, Ruschenburg I, Nagel H, Droese M |
| The Journal of pathology. 1997 ; 182 (1) : 54-61. |
| PMID 9227342 |
| MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. |
| Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX |
| Molecular cell. 2005 ; 20 (5) : 699-708. |
| PMID 16337594 |
| P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. |
| Tao W, Levine AJ |
| Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (12) : 6937-6941. |
| PMID 10359817 |
| Overexpression of the MDM2 oncogene in leukemia and lymphoma. |
| Watanabe T, Ichikawa A, Saito H, Hotta T |
| Leukemia & lymphoma. 1996 ; 21 (5-6) : 391-397. |
| PMID 9172803 |
7. Citation
| This paper should be referenced as such : |
| Villalona-Calero, MA ; Duan, W |
| MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein) |
| Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):102-104. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/MDM2ID115ch12q15.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 10 ] |
8. External links
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jan 17 19:00:25 CET 2019 |
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