Mdm2
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Overview
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and an inhibitor of p53 transcriptional activation.
Discovery and expression in tumor cells
The murine double minute (mdm2) oncogene, which codes for the Mdm2 protein, was originally cloned, along with two other genes (mdm1 and mdm3) from the transformed mouse cell line 3T3-DM. Mdm2 overexpression, in cooperation with oncogenic Ras, promotes transformation of primary rodent fibroblasts, and mdm2 expression led to tumor formation in nude mice. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an oncogene, several human tumor types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53.
Ubiquitination target: p53
The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized, the transcription of Mdm2 is also induced, resulting in higher Mdm2 protein levels.
E3 ligase activity
Mdm2 also acts as an E3 ubiquitin ligase , targeting both itself and p53 for degradation by the proteasome (see also Ubiquitin). Several lysine residues in p53 C-terminus have been identified as the sites of ubiquitination, and it has been shown that p53 protein levels are downregulated by Mdm2 in a proteasome-dependent manner. Mdm2 is capable of auto-polyubiquitination, and in complex with p300, a cooperating E3 ubiquitin ligase, is capable of polyubiquitinating p53. In this manner, Mdm2 and p53 are the members of a negative feedback control loop that keeps the level of p53 low in the absence of p53-stabilizing signals. This loop can be interfered with by kinases and genes like p14arf when p53 activation signals, including DNA damage, are high.
Structure/function details
The full-length transcript of the mdm2 gene encodes a protein of 491 amino acids with a predicted molecular weight of 56kDa. This protein contains several conserved structural domains including an N-terminal p53 interaction domain, the structure of which has been solved using x-ray crystallography. The Mdm2 protein also contains a central acidic domain (residues 230-300). The phosphorylation of residues within this domain appears to be important for regulation of Mdm2 function. In addition, this region contains nuclear export and import signals that are essential for proper nuclear-cytoplasmic trafficking of Mdm2. Another conserved domain within the Mdm2 protein is a Zinc finger domain, the function of which is poorly understood.
Mdm2 also contains a C-terminal RING domain (amino acid resdiues 430-480), which contains a Cis3-His2-Cis3 consensus that coordinates two molecules of zinc. These residues are required for zinc binding, which is essential for proper folding of the RING domain. The RING domain of Mdm2 confers E3 ubiquitin ligase activity and is sufficient for E3 ligase activity in Mdm2 RING autoubiquitination. The RING domain of Mdm2 is unique in that it incorporates a conserved Walker A or P-loop motif characteristic of nucleotide binding proteins, as well as a nucleolar localization sequence. The RING domain also binds specifically to RNA, although the function of this is poorly understood.
Regulation
There are several known mechanisms for regulation of Mdm2. One of these mechanisms is phosphorylation of the Mdm2 protein. Mdm2 is phosphorylated at multiple sites in cells. Following DNA damage, phosphorylation of Mdm2 leads to changes in protein function and stabilization of p53. Additionally, phosphorylation at certain residues within the central acidic domain of Mdm2 may stimulate its ability to target p53 for degradation. The induction of the p14arf protein, the alternate reading frame product of the p16INK4a locus, is also a mechanism of negatively regulating the p53-Mdm2 interaction. p14arf directly interacts with Mdm2 and leads to up-regulation of p53 transcriptional response. ARF sequesters Mdm2 in the nucleolus, resulting in inhibition of nuclear export and activation of p53, since nuclear export is essential for proper p53 degradation.
References
Further reading
- Cahilly-Snyder, L., Yang-Feng, T., Francke, U., and George, D. L. (1987). Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet 13, 235-244.. Entrez PubMed 3474784
- Chen, J., Lin, J., and Levine, A. J. (1995). Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol Med 1, 142-152. Entrez PubMed 8529093
- Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., and Weissman, A. M. (2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275, 8945-8951. Entrez PubMed 10722742
- Freedman, D. A., Wu, L., and Levine, A. J. (1999). Functions of the MDM2 oncoprotein. Cell Mol Life Sci 55, 96-107. Entrez PubMed 10065155
- Hay, T. J., and Meek, D. W. (2000). Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains. FEBS Lett 478, 183-186. Entrez PubMed 10922493
- Honda, R., Tanaka, H., and Yasuda, H. (1997). Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420, 25-27. Entrez PubMed 9450543
- Honda, R., and Yasuda, H. (2000). Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase. Oncogene 19, 1473-1476. Entrez PubMed 10723139
- Kubbutat, M. H., Jones, S. N., and Vousden, K. H. (1997). Regulation of p53 stability by Mdm2. Nature 387, 299-303. Entrez PubMed 9153396
- Pavletich, N. P. (1996). Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948-953. Entrez PubMed 8875929
- Meek, D. W., and Knippschild, U. (2003). Posttranslational modification of MDM2. Mol Cancer Res 1, 1017-1026. Entrez PubMed 14707285
- Midgley, C. A., Desterro, J. M., Saville, M. K., Howard, S., Sparks, A., Hay, R. T., and Lane, D. P. (2000). An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene 19, 2312-2323. Entrez PubMed 10822382
- Momand, J., Wu, H. H., and Dasgupta, G. (2000). MDM2--master regulator of the p53 tumor suppressor protein. Gene 242, 15-29. Entrez PubMed 10721693
- Momand, J., Zambetti, G. P., Olson, D. C., George, D., and Levine, A. J. (1992). The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237-1245. Entrez PubMed 1535557
- Shieh, S. Y., Ikeda, M., Taya, Y., and Prives, C. (1997). DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325-334. Entrez PubMed 9363941
- Tao, W., and Levine, A. J. (1999). P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci U S A 96, 6937-6941. Entrez PubMed 10359817
- Tao, W., and Levine, A. J. (1999). Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proc Natl Acad Sci U S A 96, 3077-3080. Entrez PubMed 10077639
External links
Oncogenes/Proto-oncogenes | |
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| Transcription factors | AP-1 (c-Fos, c-Jun) - c-Myc |
| Tyrosine kinase / Receptors | c-ErbB (HER2/neu, Her 3) - c-Kit - c-Met - c-Ret - Flt3 - |
| Other | c-Akt - c-Bcl-2 - c-Mdm2 - -c-Raf - c-Ras (HRAS) - c-Sis - c-Src - Notch - Stathmin |
Enzymes: ligases (EC 6) | |
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| 6.1 - Carbon-Oxygen | Aminoacyl tRNA synthetase |
| 6.2 - Carbon-Sulfur | Succinyl coenzyme A synthetase - Acetyl Co-A synthetase - Long fatty acyl CoA synthetase |
| 6.3 - Carbon-Nitrogen | Glutamine synthetase - Ubiquitin ligase (Von Hippel-Lindau tumor suppressor, UBE3A, Mdm2, Anaphase-promoting complex) - Glutathione synthetase - CTP synthase - Adenylosuccinate synthase - Argininosuccinate synthetase - Holocarboxylase synthetase - GMP synthase - Asparagine synthetase - Carbamoyl phosphate synthase (I , II ) |
| 6.4 - Carbon-Carbon | Carbon-carbon ligases |
| 6.5 - Phosphoric Ester | DNA ligase |
WikiDoc Research Resources for Mdm2 | |
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| Articles on Mdm2 | Most recent articles on Mdm2 • Most cited articles on Mdm2 • Review articles on Mdm2 • Articles on Mdm2 in N Eng J Med, Lancet, BMJ |
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| Evidence Based Medicine Regarding Mdm2 | Cochrane Collaboration on Mdm2 • Bandolier on Mdm2 • TRIP on Mdm2 |
| Cost Effectiveness of Mdm2 | Cost Effectiveness of Mdm2 |
| Clinical Trials Involving Mdm2 | Ongoing Trials on Mdm2 at Clinical Trials.gov • Trial results on Mdm2 • Clinical Trials on Mdm2 at Google |
| Guidelines / Policies / Government Resources (FDA/CDC) Regarding Mdm2 | US National Guidelines Clearinghouse on Mdm2 • NICE Guidance on Mdm2 • NHS PRODIGY Guidance • FDA on Mdm2 • CDC on Mdm2 |
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| Genetics, Pharmacogenomics, and Proteinomics of Mdm2 | Genetics of Mdm2 • Pharmacogenomics of Mdm2 • Proteomics of Mdm2 |
| Newstories on Mdm2 | Mdm2 in the news • Be alerted to news on Mdm2 • News trends on Mdm2 |
| Commentary on Mdm2 | Blogs on Mdm2 |
| Patient Resources on Mdm2 | Patient resources on Mdm2 • Discussion groups on Mdm2 • Patient Handouts on Mdm2 • Directions to Hospitals Treating Mdm2 • Risk calculators and risk factors for Mdm2 |
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| International Resources on Mdm2 | Mdm2 en Espanol • Mdm2 en Francais |
| Business Resources on Mdm2 | Mdm2 in the Marketplace • Patents on Mdm2 |
| Informatics Resources on Mdm2 | List of terms related to Mdm2 |
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Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
