Mdm2

Mdm2 p53 binding protein homolog (mouse)
Solution structure of Mdm2. [1]
Available structures PDB 1RV1, 1T4E, 1T4F, 1YCR, 1Z1M, 2AXI, 2C6A, 2C6B, 2F1Y, 2FOP, 2GV2, 2HDP, 2VJE, 2VJF, 3EQS, 3G03, 3IUX, 3IWY, 3JZK, 3JZR, 3JZS, 3LBK, 3LBL, 3LNJ, 3LNZ
Identifiers
Symbols	MDM2; HDMX; MGC5370; MGC71221; hdm2
External IDs	OMIM: 164785 MGI: 96952 HomoloGene: 1793 GeneCards: MDM2 Gene
Gene Ontology Molecular function • p53 binding • ubiquitin-protein ligase activity • ubiquitin-protein ligase activity • protein binding • zinc ion binding • ligase activity • enzyme binding • identical protein binding • metal ion binding Cellular component • intracellular • insoluble fraction • nucleus • nucleoplasm • nucleoplasm • nucleolus • cytoplasm • cytosol • plasma membrane • nuclear body • endocytic vesicle membrane • protein complex Biological process • cell cycle checkpoint • negative regulation of transcription from RNA polymerase II promoter • protein complex assembly • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • traversing start control point of mitotic cell cycle • synaptic transmission • positive regulation of cell proliferation • protein ubiquitination • protein ubiquitination • protein destabilization • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • protein localization to nucleus • regulation of protein catabolic process • protein ubiquitination involved in ubiquitin-dependent protein catabolic process • negative regulation of apoptosis • negative regulation of DNA damage response, signal transduction by p53 class mediator • interspecies interaction between organisms • establishment of protein localization • negative regulation of transcription, DNA-dependent • positive regulation of mitotic cell cycle • response to antibiotic • nerve growth factor receptor signaling pathway • phosphatidylinositol-mediated signaling • negative regulation of cell cycle arrest • cellular response to hypoxia Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4193	17246
Ensembl	ENSG00000135679	ENSMUSG00000020184
UniProt	Q00987	Q2L9A9
RefSeq (mRNA)	NM_002392.3	NM_010786.3
RefSeq (protein)	NP_002383.2	NP_034916.1
Location (UCSC)	Chr 12: 69.2 – 69.24 Mb	Chr 10: 117.13 – 117.15 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-imidazoline 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-ubiquitylation 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

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Further reading

• Cahilly-Snyder L, Yang-Feng T, Francke U, George DL (May 1987). "Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line". Somat. Cell Mol. Genet. 13 (3): 235–44. doi:10.1007/BF01535205. PMID 3474784. 
• Chen J, Lin J, Levine AJ (January 1995). "Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene". Mol. Med. 1 (2): 142–52. PMC 2229942. PMID 8529093. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2229942. 
• Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM (March 2000). "Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53". J. Biol. Chem. 275 (12): 8945–51. doi:10.1074/jbc.275.12.8945. PMID 10722742. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10722742. 
• Freedman DA, Wu L, Levine AJ (January 1999). "Functions of the MDM2 oncoprotein". Cell. Mol. Life Sci. 55 (1): 96–107. doi:10.1007/s000180050273. PMID 10065155. http://link.springer.de/link/service/journals/00018/bibs/9055001/90550096.htm. 
• Hay TJ, Meek DW (July 2000). "Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains". FEBS Lett. 478 (1-2): 183–6. doi:10.1016/S0014-5793(00)01850-0. PMID 10922493. http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(00)01850-0. 
• Honda, R; Tanaka, H; Yasuda, H (December 1997). "Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53". FEBS Lett. 420 (1): 25–7. doi:10.1016/S0014-5793(97)01480-4. PMID 9450543. http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(97)01480-4. 
• Honda R, Yasuda H (March 2000). "Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase". Oncogene 19 (11): 1473–6. doi:10.1038/sj.onc.1203464. PMID 10723139. 
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External links

• NLM
• Nextbio
• Genecards
• Atlas of Genetics