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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
Symbols	MDM2; HDMX; MGC71221; hdm2
External IDs	OMIM: 164785 MGI: 96952 HomoloGene: 1793 GeneCards: MDM2 Gene
Gene ontology Molecular function • ubiquitin-protein ligase activity • protein binding • zinc ion binding • ligase activity • negative regulator of basal transcription activity • enzyme binding • metal ion binding Cellular component • intracellular • nucleus • nucleoplasm • nucleolus • cytoplasm Biological process • regulation of progression through cell cycle • negative regulation of transcription from RNA polymerase II promoter • protein complex assembly • ubiquitin cycle • traversing start control point of mitotic cell cycle • negative regulation of cell proliferation • protein ubiquitination • regulation of protein catabolic process
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4193	17246
Ensembl	ENSG00000135679	ENSMUSG00000020184
UniProt	Q00987	Q2L9A9
RefSeq (mRNA)	NM_002392	NM_010786
RefSeq (protein)	NP_002383	NP_034916
Location (UCSC)	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.

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 and function

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.

Inhibitors of the MDM2-p53 interaction include the cis-imidazole analog nutlin.^[2]

Levels and stability of Mdm2 are also modulated by ubiquitylation. Mdm2 auto ubiquitylates itself, which allows for its degradation by the proteasome. Mdm2 also interacts with a ubiquitin specific protease, USP7, which can reverse Mdm2-ubiquilyation and prevent it from being degraded by the proteasome. It is interesting to note that USP7 also protects from degradation the p53 protein, which is a major target of Mdm2. Thus Mdm2 and USP7 form an intricate circuit to finely regulate the stability and activity of p53, whose levels are critical for its function.

Interactions

Mdm2 has been shown to interact with HDAC1,^[3] RPL26,^[4] FKBP3,^[5] CCNG1,^[6] HTATIP,^[7] GNL3,^[8] Death associated protein 6,^[9] PSME3,^[10] Insulin-like growth factor 1 receptor,^[11] RRM2B,^[12] FOXO4,^[13] Ribosomal protein L5,^[14][15][8] Abl gene,^[16] RYBP,^[17] HIF1A,^[18][19] PCAF,^[20] TATA binding protein,^[21][22] P73,^[23][24] CTBP2,^[25] NUMB,^[26][27] P53,^[28][29] P16,^{[14][30][31][32][9]} PSMD10,^[33] EP300,^[34] CTBP1,^[25] MDM4,^{[35][36][37][38]} RPL11,^[14][8] Promyelocytic leukemia protein,^{[39][40][41][42]} Dihydrofolate reductase,^[43] Arrestin beta 2,^[44][45][46] Arrestin beta 1^[45][46] and Ubiquitin C.^[9][47][48]

Overview of signal transduction pathways involved in apoptosis.

References

Further reading

PDB Gallery 1rv1: CRYSTAL STRUCTURE OF HUMAN MDM2 WITH AN IMIDAZOLINE INHIBITOR   1t4e: Structure of Human MDM2 in complex with a Benzodiazepine Inhibitor   1t4f: Structure of human MDM2 in complex with an optimized p53 peptide   1ycr: MDM2 BOUND TO THE TRANSACTIVATION DOMAIN OF P53   1z1m: NMR structure of unliganded MDM2   2axi: HDM2 in complex with a beta-hairpin   2c6a: SOLUTION STRUCTURE OF THE C4 ZINC-FINGER DOMAIN OF HDM2   2c6b: SOLUTION STRUCTURE OF THE C4 ZINC-FINGER DOMAIN OF HDM2   2gv2: MDM2 in complex with an 8-mer p53 peptide analogue   2hdp: Solution Structure of Hdm2 RING Finger Domain

External links

• NLM
• Nextbio
• Genecards
• Atlas of Genetics