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Mdm2




Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse)
Solution structure of Mdm2. [1]
Available structures: 1rv1, 1t4e, 1t4f, 1ycr, 1z1m, 2axi, 2c6a, 2c6b, 2gv2, 2hdp
Identifiers
Symbol(s) MDM2; HDMX; MGC71221; hdm2
External IDs OMIM: 164785 MGI: 96952 Homologene: 1793
RNA expression pattern

More reference expression data

Orthologs
Human Mouse
Entrez 4193 17246
Ensembl ENSG00000135679 ENSMUSG00000020184
Uniprot Q00987 Q2L9A9
Refseq NM_002392 (mRNA)
NP_002383 (protein)
NM_010786 (mRNA)
NP_034916 (protein)
Location Chr 12: 67.49 - 67.52 Mb Chr 10: 117.09 - 117.11 Mb
Pubmed search [1] [2]

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.

Additional recommended knowledge

Contents

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

  1. ^ Uhrinova S, Uhrin D, Powers H, et al (2005). "Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding". J. Mol. Biol. 350 (3): 587-98. doi:10.1016/j.jmb.2005.05.010. PMID 15953616.

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
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Mdm2". A list of authors is available in Wikipedia.
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