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Mdm2
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<h2 id="discovery-and-expression-in-tumor-cells">Discovery and expression in tumor cells</h2> <p>The murine <a href="/facts/Double_minute/4lgr57qI">double minute</a> (<i>mdm2</i>) <a href="/facts/Oncogene/WLFu6Ma5">oncogene</a>, 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 <a href="/facts/Ras_(protein)/JB883YoM">Ras</a>, promotes transformation of primary rodent fibroblasts, and <i>mdm2</i> expression led to tumor formation in <a href="/facts/Nude_mice/YVP9UQYa">nude mice</a>. The human homologue of this protein was later identified and is sometimes called Hdm2. Further supporting the role of mdm2 as an <a href="/facts/Oncogene/WLFu6Ma5">oncogene</a>, several human <a href="/facts/Tumor/K0ytzmPz">tumor</a> types have been shown to have increased levels of Mdm2, including soft tissue sarcomas and osteosarcomas as well as breast tumors. </p><p>An additional Mdm2 family member, Mdm4 (also called MdmX), has been discovered and is also an important negative regulator of <a href="/facts/P53/YEGULLgM">p53</a>. </p> <h2 id="ubiquitination-target-p53">Ubiquitination target: p53</h2> <p>The key target of Mdm2 is the <a href="/facts/P53/YEGULLgM">p53</a> 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 <a href="/facts/N-terminal/yKYpuaBJ">N-terminal</a> 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. </p> <h2 id="e3-ligase-activity">E3 ligase activity</h2> <p>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 <a href="/facts/Negative_feedback/G9byVgpN">negative feedback</a> loop.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> Mdm2 also acts as an <a href="/facts/Ubiquitin_ligase/8xmNaWW3">E3 ubiquitin ligase</a>, targeting both itself and p53 for degradation by the <a href="/facts/Proteasome/8vTtg2MI">proteasome</a> (see also <a href="/facts/Ubiquitin/hpulmU3m">ubiquitin</a>). Several <a href="/facts/Lysine/CEetgA9L">lysine</a> residues in p53 <a href="/facts/C-terminus/ws4scHgT">C-terminus</a> 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 <a href="/facts/Kinases/dhlHpjnD">kinases</a> and genes like <a href="/facts/P14arf/5A3GxwXx">p14arf</a> when p53 activation signals, including <a href="/facts/DNA/nB89Iauz">DNA</a> damage, are high. </p> <h2 id="structure-and-function">Structure and function</h2> <p>The full-length transcript of the mdm2 gene encodes a protein of 491 <a href="/facts/Amino_acids/WDxYwBny">amino acids</a> with a predicted molecular weight of 56kDa. This protein contains several conserved <a href="/facts/Structural_domain/oUpFcSsl">structural domains</a> including an N-terminal p53 interaction domain, the structure of which has been solved using <a href="/facts/X-ray_crystallography/WtI0F5DN">x-ray crystallography</a>. The Mdm2 protein also contains a central acidic domain (residues 230–300). The <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> 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 <a href="/facts/Zinc_finger/dWrlw4t7">zinc finger</a> domain, the function of which is poorly understood. </p><p>Mdm2 also contains a <a href="/facts/C-terminal/ws4scHgT">C-terminal</a> RING domain (amino acid residues 430–480), which contains a Cis3-His2-Cis3 consensus that coordinates two ions of <a href="/facts/Zinc/80b1qgk3">zinc</a>. These residues are required for zinc binding, which is essential for proper folding of the RING domain. The RING domain of Mdm2 confers <a href="/facts/Ubiquitin_ligase/8xmNaWW3">E3 ubiquitin ligase</a> 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 <a href="/facts/Walker_motifs/p49qD8FM">Walker A or P-loop</a> motif characteristic of <a href="/facts/Nucleotide/pQKEwlJI">nucleotide</a> binding proteins, as well as a nucleolar localization sequence. The RING domain also binds specifically to <a href="/facts/RNA/HxPeNfNj">RNA</a>, although the function of this is poorly understood. </p> <h2 id="regulation">Regulation</h2> <p>There are several known mechanisms for regulation of Mdm2. One of these mechanisms is <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> of the Mdm2 protein. Mdm2 is phosphorylated at multiple sites in cells. Following <a href="/facts/DNA/nB89Iauz">DNA</a> damage, phosphorylation of Mdm2 leads to changes in protein function and stabilization of <a href="/facts/P53/YEGULLgM">p53</a>. Additionally, phosphorylation at certain residues within the central acidic domain of Mdm2 may stimulate its ability to target p53 for degradation. <a href="/facts/HIPK2/lDWPfsVk">HIPK2</a> is a protein that regulates Mdm2 in this way. The induction of the <a href="/facts/P14arf/5A3GxwXx">p14arf</a> protein, the alternate reading frame product of the <a href="/facts/P16INK4a/ccXvc61A">p16INK4a</a> 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 <a href="/facts/Nucleolus/X7B5HKM4">nucleolus</a>, resulting in inhibition of nuclear export and activation of p53, since nuclear export is essential for proper p53 degradation. </p><p>Inhibitors of the MDM2-p53 interaction include the cis-imidazoline analog <a href="/facts/Nutlin/UMrBLxdt">nutlin</a>.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p><p>Levels and stability of Mdm2 are also modulated by ubiquitylation. Mdm2 auto ubiquitylates itself, which allows for its degradation by the <a href="/facts/Proteasome/8vTtg2MI">proteasome</a>. Mdm2 also interacts with a ubiquitin specific protease, <a href="/facts/USP7/0mqmvIsS">USP7</a>, 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. </p> <h2 id="interactions">Interactions</h2> <p>Mdm2 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/Abl_gene/h9pJd4jf">ABL1</a>,<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li> <li><a href="/facts/Arrestin_beta_1/9YQy8NTq">ARRB1</a>,<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a></li> <li><a href="/facts/Arrestin_beta_2/7qxedzQk">ARRB2</a>,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li> <li><a href="/facts/CCNG1/EMsM33zU">CCNG1</a>,<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a></li> <li><a href="/facts/CTBP1/UWDxDaVA">CTBP1</a>,<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a></li> <li><a href="/facts/CTBP2/rwWLFplJ">CTBP2</a>,<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a></li> <li><a href="/facts/Death_associated_protein_6/fwlmBARX">DAXX</a>,<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></li> <li><a href="/facts/Dihydrofolate_reductase/sAEk55jF">DHFR</a>,<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></li> <li><a href="/facts/EP300/7WU3jvjy">EP300</a>,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></li> <li><a href="/facts/C1orf173/rjwf1Vgv">ERICH3</a>,<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></li> <li><a href="/facts/FKBP3/1yR9WmGt">FKBP3</a>,<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a></li> <li><a href="/facts/FOXO4/WolKUJek">FOXO4</a>,<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></li> <li><a href="/facts/GNL3/DIF0XtRH">GNL3</a>,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a></li> <li><a href="/facts/HDAC1/6Ah3cBy1">HDAC1</a>,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></li> <li><a href="/facts/HIF1A/C2A2AXkH">HIF1A</a>,<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a></li> <li><a href="/facts/HTATIP/UkyldBkS">HTATIP</a>,<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li><a href="/facts/Insulin-like_growth_factor_1_receptor/R4c7MCqp">IGF1R</a>,<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></li> <li><a href="/facts/MDM4/JjTk7pf3">MDM4</a>,<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></li> <li><a href="/facts/NUMB_(gene)/CjHJp6Kr">NUMB</a>,<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></li> <li><a href="/facts/P16_(gene)/ccXvc61A">P16</a>,<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a></li> <li><a href="/facts/P53/YEGULLgM">P53</a>,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li> <li><a href="/facts/P73/DM92hxht">P73</a>,<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a></li> <li><a href="/facts/PCAF/mzYyuY6Q">PCAF</a>,<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a></li> <li><a href="/facts/PSMD10/TVsv1u4H">PSMD10</a>,<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a></li> <li><a href="/facts/PSME3/Lv6LpvcA">PSME3</a>,<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a></li> <li><a href="/facts/Ribosomal_protein_L5/EASy18Lo">RPL5</a>,<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a></li> <li><a href="/facts/RPL11/Re4TzeLM">RPL11</a>,<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a><a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a></li> <li><a href="/facts/Promyelocytic_leukemia_protein/QdCl05AJ">PML</a>,<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a><a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a><a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a><a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a></li> <li><a href="/facts/RPL26/GjuNDylJ">RPL26</a>,<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a></li> <li><a href="/facts/RRM2B/gWPPtjls">RRM2B</a>,<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a></li> <li><a href="/facts/RYBP/K4zIL2B2">RYBP</a>,<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a></li> <li><a href="/facts/TATA_binding_protein/3paQrYHT">TBP</a>,<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a><a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> and</li> <li><a href="/facts/Ubiquitin_C/jlyDw5JH">UBC</a>.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a><a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a><a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a></li></ul> <h2 id="mdm2-p53-independent-role">Mdm2 p53-independent role</h2> <p>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.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>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". <i>Somatic Cell and Molecular Genetics</i>. 13 (3): 235–44. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2FBF01535205">10.1007/BF01535205</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/3474784">3474784</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:27300300">27300300</a>.</li> <li>Chen J, Lin J, Levine AJ (January 1995). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229942">"Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene"</a>. <i>Molecular Medicine</i>. 1 (2): 142–52. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2FBF03401562">10.1007/BF03401562</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229942">2229942</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8529093">8529093</a>.</li> <li>Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM (March 2000). <a href="https://doi.org/10.1074%2Fjbc.275.12.8945">"Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53"</a>. <i>The Journal of Biological Chemistry</i>. 275 (12): 8945–51. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.275.12.8945">10.1074/jbc.275.12.8945</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10722742">10722742</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:25630836">25630836</a>.</li> <li>Freedman DA, Wu L, Levine AJ (January 1999). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11146946">"Functions of the MDM2 oncoprotein"</a>. <i>Cellular and Molecular Life Sciences</i>. 55 (1): 96–107. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs000180050273">10.1007/s000180050273</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11146946">11146946</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10065155">10065155</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:20034406">20034406</a>.</li> <li>Hay TJ, Meek DW (July 2000). <a href="https://doi.org/10.1016%2FS0014-5793%2800%2901850-0">"Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains"</a>. <i>FEBS Letters</i>. 478 (1–2): 183–6. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2000FEBSL.478..183H">2000FEBSL.478..183H</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0014-5793%2800%2901850-0">10.1016/S0014-5793(00)01850-0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10922493">10922493</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:40688636">40688636</a>.</li> <li>Honda R, Tanaka H, Yasuda H (December 1997). <a href="https://doi.org/10.1016%2FS0014-5793%2897%2901480-4">"Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53"</a>. <i>FEBS Letters</i>. 420 (1): 25–7. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1997FEBSL.420...25H">1997FEBSL.420...25H</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0014-5793%2897%2901480-4">10.1016/S0014-5793(97)01480-4</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9450543">9450543</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:29014813">29014813</a>.</li> <li>Honda R, Yasuda H (March 2000). <a href="https://doi.org/10.1038%2Fsj.onc.1203464">"Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase"</a>. <i>Oncogene</i>. 19 (11): 1473–6. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fsj.onc.1203464">10.1038/sj.onc.1203464</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10723139">10723139</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:8734229">8734229</a>.</li> <li>Kubbutat MH, Jones SN, Vousden KH (May 1997). "Regulation of p53 stability by Mdm2". <i>Nature</i>. 387 (6630): 299–303. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1997Natur.387..299K">1997Natur.387..299K</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F387299a0">10.1038/387299a0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9153396">9153396</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:4329670">4329670</a>.</li> <li>Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (November 1996). "Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain". <i>Science</i>. 274 (5289): 948–53. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1996Sci...274..948K">1996Sci...274..948K</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1126%2Fscience.274.5289.948">10.1126/science.274.5289.948</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8875929">8875929</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:33081920">33081920</a>.</li> <li>Meek DW, Knippschild U (December 2003). "Posttranslational modification of MDM2". <i>Molecular Cancer Research</i>. 1 (14): 1017–26. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14707285">14707285</a>.</li> <li>Midgley CA, Desterro JM, Saville MK, Howard S, Sparks A, Hay RT, Lane DP (May 2000). <a href="https://doi.org/10.1038%2Fsj.onc.1203593">"An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo"</a>. <i>Oncogene</i>. 19 (19): 2312–23. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fsj.onc.1203593">10.1038/sj.onc.1203593</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10822382">10822382</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:24814361">24814361</a>.</li> <li>Momand J, Wu HH, Dasgupta G (January 2000). 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