Mdm2: Difference between revisions

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{{Infobox_gene}}
{{PBB_Controls
'''Mouse double minute 2 homolog''' ('''MDM2''') also known as '''E3 ubiquitin-protein ligase Mdm2'''  is a [[protein]] that in humans is encoded by the ''MDM2'' [[gene]].<ref name="pmid1614537">{{cite journal | vauthors = Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B | title = Amplification of a gene encoding a p53-associated protein in human sarcomas | journal = Nature | volume = 358 | issue = 6381 | pages = 80–3 | date = July 1992 | pmid = 1614537 | doi = 10.1038/358080a0 }}</ref><ref name="pmid16905769">{{cite journal | vauthors = Wade M, Wong ET, Tang M, Stommel JM, Wahl GM | title = Hdmx modulates the outcome of p53 activation in human tumor cells | journal = The Journal of Biological Chemistry | volume = 281 | issue = 44 | pages = 33036–44 | date = November 2006 | pmid = 16905769 | doi = 10.1074/jbc.M605405200 }}</ref> Mdm2 is an important negative regulator of the [[p53]] tumor suppressor. Mdm2 protein functions both as an [[Ubiquitin ligase|E3 ubiquitin ligase]] that recognizes the [[N-terminal]] trans-activation domain (TAD) of the [[p53]] tumor suppressor and as an inhibitor of [[p53]] transcriptional activation.
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Discovery and expression in tumor cells ==
{{GNF_Protein_box
| image = Mdm2.png
| image_source = Solution structure of Mdm2. <ref>{{cite journal |author=Uhrinova S, Uhrin D, Powers H, ''et al'' |title=Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding |journal=J. Mol. Biol. |volume=350 |issue=3 |pages=587-98 |year=2005 |pmid=15953616 |doi=10.1016/j.jmb.2005.05.010}}</ref>
| PDB =
| Name = Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse)
| HGNCid = 6973
| Symbol = MDM2
| AltSymbols =; HDMX; MGC71221; hdm2
| OMIM = 164785
| ECnumber = 
| Homologene = 1793
| MGIid = 96952
| GeneAtlas_image1 = PBB_GE_MDM2_205386_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_MDM2_211832_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_MDM2_217373_x_at_tn.png
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = 07:33, 9 October 2007 (UTC)
| Function = {{GNF_GO|id=GO:0004842 |text = ubiquitin-protein ligase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016874 |text = ligase activity}} {{GNF_GO|id=GO:0017163 |text = negative regulator of basal transcription activity}} {{GNF_GO|id=GO:0019899 |text = enzyme binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005654 |text = nucleoplasm}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0006461 |text = protein complex assembly}} {{GNF_GO|id=GO:0006512 |text = ubiquitin cycle}} {{GNF_GO|id=GO:0007089 |text = traversing start control point of mitotic cell cycle}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0016567 |text = protein ubiquitination}} {{GNF_GO|id=GO:0042176 |text = regulation of protein catabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4193
    | Hs_Ensembl = ENSG00000135679
    | Hs_RefseqProtein = NP_002383
    | Hs_RefseqmRNA = NM_002392
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 67488247
    | Hs_GenLoc_end = 67520481
    | Hs_Uniprot = Q00987
    | Mm_EntrezGene = 17246
    | Mm_Ensembl = ENSMUSG00000020184
    | Mm_RefseqmRNA = NM_010786
    | Mm_RefseqProtein = NP_034916
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 117091888
    | Mm_GenLoc_end = 117113704
    | Mm_Uniprot = Q2L9A9
  }}
}}
{{SI}}
{{CMG}}


==Overview==
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 (protein)|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. The MDM2 oncoprotein [[ubiquitin]]ates and antagonizes [[p53]] but may also carry out p53-independent functions. MDM2 supports the [[polycomb-group proteins|Polycomb]]-mediated repression of lineage-specific genes, independent of p53. MDM2 depletion in the absence of p53 promoted the [[Cellular differentiation|differentiation]] of human [[mesenchymal stem cells]] and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 ([[PRC2]]) and its catalytic component [[EZH2]]. MDM2 physically associated with EZH2 on [[chromatin]], enhancing the trimethylation of [[histone]] 3 at [[lysine]] 27 (H3K27)and the [[ubiquitin]]ation of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase [[RING1|Ring1]]B/[[RNF2]] further induced these genes and synthetically arrested [[cell proliferation]].<ref>{{cite journal | vauthors = Wienken M, Dickmanns A, Nemajerova A, Kramer D, Najafova Z, Weiss M, Karpiuk O, Kassem M, Zhang Y, Lozano G, Johnsen SA, Moll UM, Zhang X, Dobbelstein M | title = MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53 | journal = Molecular Cell | volume = 61 | issue = 1 | pages = 68–83 | date = January 2016 | pmid = 26748827 | doi = 10.1016/j.molcel.2015.12.008 }}</ref>
'''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 [[Ubiquitin ligase|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==
An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of [[p53]].
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]].
 
MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53-overactivation-dependent cell death, referred to as podoptosis. Podoptosis is [[caspase]]-independent and, therefore, different from [[apoptosis]]. The mitogenic role of MDM2 is also needed for [[wound healing]] upon [[Tissue (biology)|tissue]] injury, while MDM2 inhibition impairs re-[[epithelialization]] upon epithelial damage. In addition, MDM2 has p53-independent [[transcription factor]]-like effects in nuclear factor-kappa beta ([[NFκB]]) activation. Therefore, MDM2 promotes tissue [[inflammation]] and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. So, MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative [[autoimmunity]], such as [[systemic lupus erythematosus]] or [[crescentic glomerulonephritis]].<ref>{{cite journal | vauthors = Ebrahim M, Mulay SR, Anders HJ, Thomasova D | title = MDM2 beyond cancer: podoptosis, development, inflammation, and tissue regeneration | journal = Histology and Histopathology | volume = 30 | issue = 11 | pages = 1271–82 | date = November 2015 | pmid = 26062755 | doi = 10.14670/HH-11-636 }}</ref>


==Ubiquitination target: 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.  
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 ==
The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. MDM2 binds and ubiquitinates p53, facilitating it for degradation. p53 can induce transcription of MDM2, generating a negative feedback loop.<ref>{{cite journal | vauthors = Huun J, Gansmo LB, Mannsåker B, Iversen GT, Sommerfelt-Pettersen J, Øvrebø JI, Lønning PE, Knappskog S | title = The Functional Roles of the MDM2 Splice Variants P2-MDM2-10 and MDM2-∆5 in Breast Cancer Cells | journal = Translational Oncology | volume = 10 | issue = 5 | pages = 806–817 | date = October 2017 | pmid = 28844019 | pmc = 5576977 | doi = 10.1016/j.tranon.2017.07.006 }}</ref> Mdm2 also acts as an [[Ubiquitin ligase|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 [[Ubiquitin ligase|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 domain]]s 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 [[Ubiquitin ligase|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 motifs|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. [[HIPK2]] is a protein that regulates Mdm2 in this way. 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.


==E3 ligase activity==
Inhibitors of the MDM2-p53 interaction include the cis-imidazoline analog [[nutlin]].<ref name="Nutlin">{{cite journal | vauthors = Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA | title = In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 | journal = Science | volume = 303 | issue = 5659 | pages = 844–8 | date = February 2004 | pmid = 14704432 | doi = 10.1126/science.1092472 }}</ref>
Mdm2 also acts as an [[Ubiquitin ligase|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 [[Ubiquitin ligase|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==
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.  [[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.
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 domain]]s 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 [[Ubiquitin ligase|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.
== Interactions ==


==Regulation==
[[Image:Signal transduction pathways.svg|350px|thumb|Right|Overview of signal transduction pathways involved in [[apoptosis]].]]
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.  
Mdm2 has been shown to [[Protein-protein interaction|interact]] with:
 
{{div col|colwidth=10em}}
* [[Abl gene|ABL1]],<ref name="pmid12110584">{{cite journal | vauthors = Goldberg Z, Vogt Sionov R, Berger M, Zwang Y, Perets R, Van Etten RA, Oren M, Taya Y, Haupt Y | title = Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation | journal = The EMBO Journal | volume = 21 | issue = 14 | pages = 3715–27 | date = July 2002 | pmid = 12110584 | pmc = 125401 | doi = 10.1093/emboj/cdf384 }}</ref>
* [[Arrestin beta 1|ARRB1]],<ref name=pmid12538596/><ref name=pmid18544533/>
* [[Arrestin beta 2|ARRB2]],<ref name="pmid12538596">{{cite journal | vauthors = Wang P, Wu Y, Ge X, Ma L, Pei G | title = Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11648–53 | date = March 2003 | pmid = 12538596 | doi = 10.1074/jbc.M208109200 }}</ref><ref name="pmid18544533">{{cite journal | vauthors = Shenoy SK, Xiao K, Venkataramanan V, Snyder PM, Freedman NJ, Weissman AM | title = Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor | journal = The Journal of Biological Chemistry | volume = 283 | issue = 32 | pages = 22166–76 | date = August 2008 | pmid = 18544533 | pmc = 2494938 | doi = 10.1074/jbc.M709668200 }}</ref><ref name="pmid12488444">{{cite journal | vauthors = Wang P, Gao H, Ni Y, Wang B, Wu Y, Ji L, Qin L, Ma L, Pei G | title = Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 6363–70 | date = February 2003 | pmid = 12488444 | doi = 10.1074/jbc.M210350200 }}</ref>
* [[CCNG1]],<ref name="pmid12556559">{{cite journal | vauthors = Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE | title = Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways | journal = Molecular Cancer Research | volume = 1 | issue = 3 | pages = 195–206 | date = January 2003 | pmid = 12556559 | doi =  }}</ref>
* [[CTBP1]],<ref name=pmid12867035/>
* [[CTBP2]],<ref name="pmid12867035">{{cite journal | vauthors = Mirnezami AH, Campbell SJ, Darley M, Primrose JN, Johnson PW, Blaydes JP | title = Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription | journal = Current Biology | volume = 13 | issue = 14 | pages = 1234–9 | date = July 2003 | pmid = 12867035 | doi = 10.1016/S0960-9822(03)00454-8 }}</ref>
* [[Death associated protein 6|DAXX]],<ref name="pmid18583933">{{cite journal | vauthors = Ivanchuk SM, Mondal S, Rutka JT | title = p14ARF interacts with DAXX: effects on HDM2 and p53 | journal = Cell Cycle | volume = 7 | issue = 12 | pages = 1836–50 | date = June 2008 | pmid = 18583933 | doi = 10.4161/cc.7.12.6025 }}</ref>
* [[Dihydrofolate reductase|DHFR]],<ref name="pmid18451149">{{cite journal | vauthors = Maguire M, Nield PC, Devling T, Jenkins RE, Park BK, Polański R, Vlatković N, Boyd MT | title = MDM2 regulates dihydrofolate reductase activity through monoubiquitination | journal = Cancer Research | volume = 68 | issue = 9 | pages = 3232–42 | date = May 2008 | pmid = 18451149 | pmc = 3536468 | doi = 10.1158/0008-5472.CAN-07-5271 }}</ref>
* [[EP300]],<ref name="pmid9809062">{{cite journal | vauthors = Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao ZX, Kumar S, Howley PM, Livingston DM | title = p300/MDM2 complexes participate in MDM2-mediated p53 degradation | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 405–15 | date = October 1998 | pmid = 9809062 | doi = 10.1016/S1097-2765(00)80140-9 }}</ref>
* [[C1orf173|ERICH3]],<ref>{{cite journal | vauthors = Miyamoto-Sato E, Fujimori S, Ishizaka M, Hirai N, Masuoka K, Saito R, Ozawa Y, Hino K, Washio T, Tomita M, Yamashita T, Oshikubo T, Akasaka H, Sugiyama J, Matsumoto Y, Yanagawa H | title = A comprehensive resource of interacting protein regions for refining human transcription factor networks | journal = PLoS One | volume = 5 | issue = 2 | pages = e9289 | date = Feb 2010 | pmid = 20195357 | pmc = 2827538 | doi = 10.1371/journal.pone.0009289 }}</ref>
* [[FKBP3]],<ref name="pmid19166840">{{cite journal | vauthors = Ochocka AM, Kampanis P, Nicol S, Allende-Vega N, Cox M, Marcar L, Milne D, Fuller-Pace F, Meek D | title = FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53 | journal = FEBS Letters | volume = 583 | issue = 4 | pages = 621–6 | date = February 2009 | pmid = 19166840 | doi = 10.1016/j.febslet.2009.01.009 }}</ref>
* [[FOXO4]],<ref name="pmid18665269">{{cite journal | vauthors = Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM | title = Mdm2 induces mono-ubiquitination of FOXO4 | journal = PLoS One | volume = 3 | issue = 7 | pages = e2819 | year = 2008 | pmid = 18665269 | pmc = 2475507 | doi = 10.1371/journal.pone.0002819 }}</ref>
* [[GNL3]],<ref name="pmid18426907">{{cite journal | vauthors = Dai MS, Sun XX, Lu H | title = Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2 | journal = Molecular and Cellular Biology | volume = 28 | issue = 13 | pages = 4365–76 | date = July 2008 | pmid = 18426907 | pmc = 2447154 | doi = 10.1128/MCB.01662-07 }}</ref>
* [[HDAC1]],<ref name="pmid12426395">{{cite journal | vauthors = Ito A, Kawaguchi Y, Lai CH, Kovacs JJ, Higashimoto Y, Appella E, Yao TP | title = MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation | journal = The EMBO Journal | volume = 21 | issue = 22 | pages = 6236–45 | date = November 2002 | pmid = 12426395 | pmc = 137207 | doi = 10.1093/emboj/cdf616 }}</ref>
* [[HIF1A]],<ref name="pmid12606552">{{cite journal | vauthors = Chen D, Li M, Luo J, Gu W | title = Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function | journal = The Journal of Biological Chemistry | volume = 278 | issue = 16 | pages = 13595–8 | date = April 2003 | pmid = 12606552 | doi = 10.1074/jbc.C200694200 }}</ref><ref name="pmid10640274">{{cite journal | vauthors = Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A | title = Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha | journal = Genes & Development | volume = 14 | issue = 1 | pages = 34–44 | date = January 2000 | pmid = 10640274 | pmc = 316350 | doi = 10.1101/gad.14.1.34 }}</ref>
* [[HTATIP]],<ref name="pmid11927554">{{cite journal | vauthors = Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S, Trouche D | title = Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation | journal = The EMBO Journal | volume = 21 | issue = 7 | pages = 1704–12 | date = April 2002 | pmid = 11927554 | pmc = 125958 | doi = 10.1093/emboj/21.7.1704 }}</ref>
* [[Insulin-like growth factor 1 receptor|IGF1R]],<ref name="pmid18632619">{{cite journal | vauthors = Sehat B, Andersson S, Girnita L, Larsson O | title = Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis | journal = Cancer Research | volume = 68 | issue = 14 | pages = 5669–77 | date = July 2008 | pmid = 18632619 | doi = 10.1158/0008-5472.CAN-07-6364 }}</ref>
* [[MDM4]],<ref name="pmid12483531">{{cite journal | vauthors = Kadakia M, Brown TL, McGorry MM, Berberich SJ | title = MdmX inhibits Smad transactivation | journal = Oncogene | volume = 21 | issue = 57 | pages = 8776–85 | date = December 2002 | pmid = 12483531 | doi = 10.1038/sj.onc.1205993 }}</ref><ref name="pmid10218570">{{cite journal | vauthors = Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M | title = MDM2 interacts with MDMX through their RING finger domains | journal = FEBS Letters | volume = 447 | issue = 1 | pages = 5–9 | date = March 1999 | pmid = 10218570 | doi = 10.1016/S0014-5793(99)00254-9 }}</ref><ref name="pmid12393902">{{cite journal | vauthors = Badciong JC, Haas AL | title = MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination | journal = The Journal of Biological Chemistry | volume = 277 | issue = 51 | pages = 49668–75 | date = December 2002 | pmid = 12393902 | doi = 10.1074/jbc.M208593200 }}</ref><ref name="pmid18219319">{{cite journal | vauthors = Linke K, Mace PD, Smith CA, Vaux DL, Silke J, Day CL | title = Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans | journal = Cell Death and Differentiation | volume = 15 | issue = 5 | pages = 841–8 | date = May 2008 | pmid = 18219319 | doi = 10.1038/sj.cdd.4402309 }}</ref>
* [[NUMB (gene)|NUMB]],<ref name="pmid12646252">{{cite journal | vauthors = Yogosawa S, Miyauchi Y, Honda R, Tanaka H, Yasuda H | title = Mammalian Numb is a target protein of Mdm2, ubiquitin ligase | journal = Biochemical and Biophysical Research Communications | volume = 302 | issue = 4 | pages = 869–72 | date = March 2003 | pmid = 12646252 | doi = 10.1016/S0006-291X(03)00282-1 }}</ref><ref name="pmid18172499">{{cite journal | vauthors = Colaluca IN, Tosoni D, Nuciforo P, Senic-Matuglia F, Galimberti V, Viale G, Pece S, Di Fiore PP | title = NUMB controls p53 tumour suppressor activity | journal = Nature | volume = 451 | issue = 7174 | pages = 76–80 | date = January 2008 | pmid = 18172499 | doi = 10.1038/nature06412 }}</ref>
* [[P16 (gene)|P16]],<ref name=pmid18583933/><ref name=pmid14612427/><ref name="pmid9529249">{{cite journal | vauthors = Zhang Y, Xiong Y, Yarbrough WG | title = ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways | journal = Cell | volume = 92 | issue = 6 | pages = 725–34 | date = March 1998 | pmid = 9529249 | doi = 10.1016/S0092-8674(00)81401-4 }}</ref><ref name="pmid12085228">{{cite journal | vauthors = Clark PA, Llanos S, Peters G | title = Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2 | journal = Oncogene | volume = 21 | issue = 29 | pages = 4498–507 | date = July 2002 | pmid = 12085228 | doi = 10.1038/sj.onc.1205558 }}</ref><ref name="pmid9529248">{{cite journal | vauthors = Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA | title = The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 | journal = Cell | volume = 92 | issue = 6 | pages = 713–23 | date = March 1998 | pmid = 9529248 | doi = 10.1016/S0092-8674(00)81400-2 }}</ref>
* [[P53]],<ref name="pmid9153395">{{cite journal | vauthors = Haupt Y, Maya R, Kazaz A, Oren M | title = Mdm2 promotes the rapid degradation of p53 | journal = Nature | volume = 387 | issue = 6630 | pages = 296–9 | date = May 1997 | pmid = 9153395 | doi = 10.1038/387296a0 }}</ref><ref name="pmid9450543">{{cite journal | vauthors = Honda R, Tanaka H, Yasuda H | title = Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 | journal = FEBS Letters | volume = 420 | issue = 1 | pages = 25–7 | date = December 1997 | pmid = 9450543 | doi = 10.1016/S0014-5793(97)01480-4 }}</ref>
* [[P73]],<ref name="pmid10435614">{{cite journal | vauthors = Bálint E, Bates S, Vousden KH | title = Mdm2 binds p73 alpha without targeting degradation | journal = Oncogene | volume = 18 | issue = 27 | pages = 3923–9 | date = July 1999 | pmid = 10435614 | doi = 10.1038/sj.onc.1202781 }}</ref><ref name="pmid10207051">{{cite journal | vauthors = Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin WG, Oren M, Chen J, Lu H | title = MDM2 suppresses p73 function without promoting p73 degradation | journal = Molecular and Cellular Biology | volume = 19 | issue = 5 | pages = 3257–66 | date = May 1999 | pmid = 10207051 | pmc = 84120 | doi =  10.1128/mcb.19.5.3257}}</ref>
* [[PCAF]],<ref name="pmid12068014">{{cite journal | vauthors = Jin Y, Zeng SX, Dai MS, Yang XJ, Lu H | title = MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30838–43 | date = August 2002 | pmid = 12068014 | doi = 10.1074/jbc.M204078200 }}</ref>
* [[PSMD10]],<ref name="pmid18332869">{{cite journal | vauthors = Qiu W, Wu J, Walsh EM, Zhang Y, Chen CY, Fujita J, Xiao ZX | title = Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells | journal = Oncogene | volume = 27 | issue = 29 | pages = 4034–43 | date = July 2008 | pmid = 18332869 | doi = 10.1038/onc.2008.43 }}</ref>
* [[PSME3]],<ref name="pmid18309296">{{cite journal | vauthors = Zhang Z, Zhang R | title = Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation | journal = The EMBO Journal | volume = 27 | issue = 6 | pages = 852–64 | date = March 2008 | pmid = 18309296 | pmc = 2265109 | doi = 10.1038/emboj.2008.25 }}</ref>
* [[Ribosomal protein L5|RPL5]],<ref name=pmid18426907/><ref name="pmid14612427">{{cite journal | vauthors = Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, Xiong Y | title = Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway | journal = Molecular and Cellular Biology | volume = 23 | issue = 23 | pages = 8902–12 | date = December 2003 | pmid = 14612427 | pmc = 262682 | doi = 10.1128/MCB.23.23.8902-8912.2003 }}</ref><ref name="pmid7935455">{{cite journal | vauthors = Marechal V, Elenbaas B, Piette J, Nicolas JC, Levine AJ | title = The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes | journal = Molecular and Cellular Biology | volume = 14 | issue = 11 | pages = 7414–20 | date = November 1994 | pmid = 7935455 | pmc = 359276 | doi =  10.1128/mcb.14.11.7414}}</ref>
* [[RPL11]],<ref name=pmid18426907/><ref name=pmid14612427/>
* [[Promyelocytic leukemia protein|PML]],<ref name="pmid15195100">{{cite journal | vauthors = Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP | title = PML regulates p53 stability by sequestering Mdm2 to the nucleolus | journal = Nature Cell Biology | volume = 6 | issue = 7 | pages = 665–72 | date = July 2004 | pmid = 15195100 | doi = 10.1038/ncb1147 }}</ref><ref name="pmid14507915">{{cite journal | vauthors = Zhu H, Wu L, Maki CG | title = MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 49 | pages = 49286–92 | date = December 2003 | pmid = 14507915 | doi = 10.1074/jbc.M308302200 }}</ref><ref name="pmid12915590">{{cite journal | vauthors = Kurki S, Latonen L, Laiho M | title = Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization | journal = Journal of Cell Science | volume = 116 | issue = Pt 19 | pages = 3917–25 | date = October 2003 | pmid = 12915590 | doi = 10.1242/jcs.00714 }}</ref><ref name="pmid12759344">{{cite journal | vauthors = Wei X, Yu ZK, Ramalingam A, Grossman SR, Yu JH, Bloch DB, Maki CG | title = Physical and functional interactions between PML and MDM2 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 29288–97 | date = August 2003 | pmid = 12759344 | doi = 10.1074/jbc.M212215200 }}</ref>
* [[RPL26]],<ref name="pmid18951086">{{cite journal | vauthors = Ofir-Rosenfeld Y, Boggs K, Michael D, Kastan MB, Oren M | title = Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26 | journal = Molecular Cell | volume = 32 | issue = 2 | pages = 180–9 | date = October 2008 | pmid = 18951086 | pmc = 2587494 | doi = 10.1016/j.molcel.2008.08.031 }}</ref>
* [[RRM2B]],<ref name="pmid19015526">{{cite journal | vauthors = Chang L, Zhou B, Hu S, Guo R, Liu X, Jones SN, Yen Y | title = ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 47 | pages = 18519–24 | date = November 2008 | pmid = 19015526 | pmc = 2587585 | doi = 10.1073/pnas.0803313105 }}</ref>
* [[RYBP]],<ref name="pmid19098711">{{cite journal | vauthors = Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R | title = RYBP stabilizes p53 by modulating MDM2 | journal = EMBO Reports | volume = 10 | issue = 2 | pages = 166–72 | date = February 2009 | pmid = 19098711 | pmc = 2637313 | doi = 10.1038/embor.2008.231 }}</ref>
* [[TATA binding protein|TBP]],<ref name="pmid9388200">{{cite journal | vauthors = Léveillard T, Wasylyk B | title = The MDM2 C-terminal region binds to TAFII250 and is required for MDM2 regulation of the cyclin A promoter | journal = The Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30651–61 | date = December 1997 | pmid = 9388200 | doi = 10.1074/jbc.272.49.30651 }}</ref><ref name="pmid9271120">{{cite journal | vauthors = Thut CJ, Goodrich JA, Tjian R | title = Repression of p53-mediated transcription by MDM2: a dual mechanism | journal = Genes & Development | volume = 11 | issue = 15 | pages = 1974–86 | date = August 1997 | pmid = 9271120 | pmc = 316412 | doi = 10.1101/gad.11.15.1974 }}</ref> and
* [[Ubiquitin C|UBC]].<ref name=pmid18583933/><ref name="pmid18566590">{{cite journal | vauthors = Song MS, Song SJ, Kim SY, Oh HJ, Lim DS | title = The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex | journal = The EMBO Journal | volume = 27 | issue = 13 | pages = 1863–74 | date = July 2008 | pmid = 18566590 | pmc = 2486425 | doi = 10.1038/emboj.2008.115 }}</ref><ref name="pmid18382127">{{cite journal | vauthors = Yang W, Dicker DT, Chen J, El-Deiry WS | title = CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2 | journal = Cell Cycle | volume = 7 | issue = 5 | pages = 670–82 | date = March 2008 | pmid = 18382127 | doi = 10.4161/cc.7.5.5701 }}</ref>
{{Div col end}}
 
== Mdm2 p53-independent role ==
Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability. These data demonstrated Mdm2-induced genome instability can be mediated through Mdm2:Nbs1 interactions and independent from its association with p53.


== References ==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin|2}}
{{refbegin|33em}}
*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}}
* {{cite journal | vauthors = Cahilly-Snyder L, Yang-Feng T, Francke U, George DL | title = Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line | journal = Somatic Cell and Molecular Genetics | volume = 13 | issue = 3 | pages = 235–44 | date = May 1987 | pmid = 3474784 | doi = 10.1007/BF01535205 }}
* 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}}
* {{cite journal | vauthors = Chen J, Lin J, Levine AJ | title = Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene | journal = Molecular Medicine | volume = 1 | issue = 2 | pages = 142–52 | date = January 1995 | pmid = 8529093 | pmc = 2229942 }}
*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}}
* {{cite journal | vauthors = Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM | title = Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 12 | pages = 8945–51 | date = March 2000 | pmid = 10722742 | doi = 10.1074/jbc.275.12.8945 }}
*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}}
* {{cite journal | vauthors = Freedman DA, Wu L, Levine AJ | title = Functions of the MDM2 oncoprotein | journal = Cellular and Molecular Life Sciences | volume = 55 | issue = 1 | pages = 96–107 | date = January 1999 | pmid = 10065155 | doi = 10.1007/s000180050273 }}
*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}}
* {{cite journal | vauthors = Hay TJ, Meek DW | title = Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains | journal = FEBS Letters | volume = 478 | issue = 1-2 | pages = 183–6 | date = July 2000 | pmid = 10922493 | doi = 10.1016/S0014-5793(00)01850-0 }}
*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}}
* {{cite journal | vauthors = Honda R, Tanaka H, Yasuda H | title = Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 | journal = FEBS Letters | volume = 420 | issue = 1 | pages = 25–7 | date = December 1997 | pmid = 9450543 | doi = 10.1016/S0014-5793(97)01480-4 }}
*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}}
* {{cite journal | vauthors = Honda R, Yasuda H | title = Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase | journal = Oncogene | volume = 19 | issue = 11 | pages = 1473–6 | date = March 2000 | pmid = 10723139 | doi = 10.1038/sj.onc.1203464 }}
*Kubbutat, M. H., Jones, S. N., and Vousden, K. H. (1997). Regulation of p53 stability by Mdm2. Nature 387, 299-303. {{Entrez Pubmed|9153396 }}
* {{cite journal | vauthors = Kubbutat MH, Jones SN, Vousden KH | title = Regulation of p53 stability by Mdm2 | journal = Nature | volume = 387 | issue = 6630 | pages = 299–303 | date = May 1997 | pmid = 9153396 | doi = 10.1038/387299a0 }}
*Pavletich, N. P. (1996). Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948-953. {{Entrez Pubmed|8875929}}
* {{cite journal | vauthors = Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP | title = Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain | journal = Science | volume = 274 | issue = 5289 | pages = 948–53 | date = November 1996 | pmid = 8875929 | doi = 10.1126/science.274.5289.948 }}
*Meek, D. W., and Knippschild, U. (2003). Posttranslational modification of MDM2. Mol Cancer Res 1, 1017-1026. {{Entrez Pubmed|14707285}}
* {{cite journal | vauthors = Meek DW, Knippschild U | title = Posttranslational modification of MDM2 | journal = Molecular Cancer Research | volume = 1 | issue = 14 | pages = 1017–26 | date = December 2003 | pmid = 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}}
* {{cite journal | vauthors = Midgley CA, Desterro JM, Saville MK, Howard S, Sparks A, Hay RT, Lane DP | title = An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo | journal = Oncogene | volume = 19 | issue = 19 | pages = 2312–23 | date = May 2000 | pmid = 10822382 | doi = 10.1038/sj.onc.1203593 }}
*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}}
* {{cite journal | vauthors = Momand J, Wu HH, Dasgupta G | title = MDM2--master regulator of the p53 tumor suppressor protein | journal = Gene | volume = 242 | issue = 1-2 | pages = 15–29 | date = January 2000 | pmid = 10721693 | doi = 10.1016/S0378-1119(99)00487-4 }}
*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}}
* {{cite journal | vauthors = Momand J, Zambetti GP, Olson DC, George D, Levine AJ | title = The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation | journal = Cell | volume = 69 | issue = 7 | pages = 1237–45 | date = June 1992 | pmid = 1535557 | doi = 10.1016/0092-8674(92)90644-R }}
*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}}
* {{cite journal | vauthors = Shieh SY, Ikeda M, Taya Y, Prives C | title = DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2 | journal = Cell | volume = 91 | issue = 3 | pages = 325–34 | date = October 1997 | pmid = 9363941 | doi = 10.1016/S0092-8674(00)80416-X }}
*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}}
* {{cite journal | vauthors = Tao W, Levine AJ | title = P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 12 | pages = 6937–41 | date = June 1999 | pmid = 10359817 | pmc = 22020 | doi = 10.1073/pnas.96.12.6937 }}
*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}}
* {{cite journal | vauthors = Tao W, Levine AJ | title = Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3077–80 | date = March 1999 | pmid = 10077639 | pmc = 15897 | doi = 10.1073/pnas.96.6.3077 }}
{{refend}}
{{refend}}


==Resources==
== External links ==
* {{MeshName|Mdm2+Protein}}
* [https://www.nlm.nih.gov/cgi/mesh/2008/MB_cgi?mode=&term=Mdm2+Protein NLM]
* [https://www.ncbi.nlm.nih.gov/gene/4193 NCBI-Gene]
* [http://www.nextbio.com/b/home/home.nb?q=MDM2 Nextbio]
* [https://www.nlm.nih.gov/cgi/mesh/2008/MB_cgi?mode=&term=Mdm2+Protein Genecards]
* [http://atlasgeneticsoncology.org/Genes/MDM2ID115ch12q15.html Atlas of Genetics]


{{PDB Gallery|geneid=4193}}
{{Oncogenes}}
{{Oncogenes}}
{{Ligases}}
{{Ligases}}
 
{{Posttranslational modification}}


[[Category:Proteins]]
[[Category:Proteins]]
[[Category:Oncology]]
[[Category:Oncogenes]]
 
[[Category:Human proteins]]
{{WH}}
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Latest revision as of 14:51, 4 January 2019

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Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene.[1][2] Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as 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. The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. MDM2 depletion in the absence of p53 promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 (H3K27)and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation.[3]

An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of p53.

MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53-overactivation-dependent cell death, referred to as podoptosis. Podoptosis is caspase-independent and, therefore, different from apoptosis. The mitogenic role of MDM2 is also needed for wound healing upon tissue injury, while MDM2 inhibition impairs re-epithelialization upon epithelial damage. In addition, MDM2 has p53-independent transcription factor-like effects in nuclear factor-kappa beta (NFκB) activation. Therefore, MDM2 promotes tissue inflammation and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. So, MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative autoimmunity, such as systemic lupus erythematosus or crescentic glomerulonephritis.[4]

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

The E3 ubiquitin ligase MDM2 is a negative regulator of the p53 tumor suppressor protein. MDM2 binds and ubiquitinates p53, facilitating it for degradation. p53 can induce transcription of MDM2, generating a negative feedback loop.[5] 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. HIPK2 is a protein that regulates Mdm2 in this way. 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.[6]

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. 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

File:Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

Mdm2 has been shown to interact with:

Mdm2 p53-independent role

Mdm2 overexpression was shown to inhibit DNA double-strand break repair mediated through a novel, direct interaction between Mdm2 and Nbs1 and independent of p53. Regardless of p53 status, increased levels of Mdm2, but not Mdm2 lacking its Nbs1-binding domain, caused delays in DNA break repair, chromosomal abnormalities, and genome instability. These data demonstrated Mdm2-induced genome instability can be mediated through Mdm2:Nbs1 interactions and independent from its association with p53.

References

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Further reading

External links

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