MDM2

Summary

Gene Symbol: MDM2
Description: MDM2 proto-oncogene
Alias: ACTFS, HDMX, hdm2, E3 ubiquitin-protein ligase Mdm2, MDM2 oncogene, E3 ubiquitin protein ligase, MDM2 proto-oncogene, E3 ubiquitin protein ligase, Mdm2, p53 E3 ubiquitin protein ligase homolog, Mdm2, transformed 3T3 cell double minute 2, p53 binding protein, double minute 2, human homolog of; p53-binding protein, oncoprotein Mdm2
Species: human
Products:     MDM2

Top Publications

  1. Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, et al. Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell. 2010;18:147-59 pubmed publisher
    b>Mdm2 is the major negative regulator of the p53 pathway...
  2. Ezzikouri S, Essaid El Feydi A, Afifi R, Benazzouz M, Hassar M, Pineau P, et al. Impact of TP53 codon 72 and MDM2 promoter 309 allelic dosage in a Moroccan population with hepatocellular carcinoma. Int J Biol Markers. 2011;26:229-33 pubmed publisher
    Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been shown to play a role in the predisposition to many cancers...
  3. Xu X, Fang Y, Lee T, Forrest D, Gregory Evans C, Almeida D, et al. Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell. 2009;137:1018-31 pubmed publisher
    ..We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 ..
  4. Pei D, Zhang Y, Zheng J. Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget. 2012;3:228-35 pubmed
    ..b>Mdm2 and Mdmx are recognized as the main p53 negative regulators...
  5. Zhou X, Hao Q, Liao J, Zhang Q, Lu H. Ribosomal protein S14 unties the MDM2-p53 loop upon ribosomal stress. Oncogene. 2013;32:388-96 pubmed publisher
    The MDM2-p53 feedback loop is crucially important for restricting p53 level and activity during normal cell growth and proliferation, and is thus subjected to dynamic regulation in order for cells to activate p53 upon various stress ..
  6. Sasaki M, Kawahara K, Nishio M, Mimori K, Kogo R, Hamada K, et al. Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nat Med. 2011;17:944-51 pubmed publisher
    ..Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1...
  7. Hock A, Vigneron A, Carter S, Ludwig R, Vousden K. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J. 2011;30:4921-30 pubmed publisher
    ..The stability of p53 is tightly regulated by ubiquitin-dependent degradation, driven mainly by the ubiquitin ligase MDM2. In this study, we have identified USP42 as a DUB that interacts with and deubiquitinates p53...
  8. Liu J, Zheng Y, Lei D, Liu D, Xu F, Jin T, et al. MDM2 309T>G polymorphism and risk of squamous cell carcinomas of head and neck: a meta-analysis. Asian Pac J Cancer Prev. 2011;12:1899-903 pubmed
    Several studies have reported influence of the murine double minute 2 (MDM2) 309T>G polymorphism on head and neck squamous cell carcinoma (HNSCC) susceptibility. However, the results remain controversial and ambiguous...
  9. Zhang X, Wang W, Wang H, Wang M, Xu W, Zhang R. Identification of ribosomal protein S25 (RPS25)-MDM2-p53 regulatory feedback loop. Oncogene. 2013;32:2782-91 pubmed publisher
    There is an increasing interest in determining the role of ribosomal proteins (RPs) in the regulation of MDM2-p53 pathway in coordinating cellular response to stress...

More Information

Publications375 found, 100 shown here

  1. Kang S, Wang D, Li W, Wang N, Zhou R, Sun D, et al. Association of p73 and MDM2 polymorphisms with the risk of epithelial ovarian cancer in Chinese women. Int J Gynecol Cancer. 2009;19:572-7 pubmed publisher
    This study was to investigate the association of p73 G4C14-to-A4T14 and Murine Double Minute2 (MDM2) 309T/G, Del1518+/- single nucleotide polymorphisms with the risk of epithelial ovarian cancer (EOC) in Chinese...
  2. Bernal F, Wade M, Godes M, Davis T, Whitehead D, Kung A, et al. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. 2010;18:411-22 pubmed publisher
    ..However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53...
  3. Yuan J, Luo K, Zhang L, Cheville J, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384-96 pubmed publisher
    ..Ubiquitination by the E3 ubiquitin ligase Mdm2 is the major regulatory mechanism of p53, which induces p53 nuclear export and degradation...
  4. Wu H, Pomeroy S, Ferreira M, Teider N, Mariani J, Nakayama K, et al. UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat Med. 2011;17:347-55 pubmed publisher
    ..factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice)...
  5. Ryan B, Calhoun K, Pine S, Bowman E, Robles A, Ambs S, et al. MDM2 SNP285 does not antagonize the effect of SNP309 in lung cancer. Int J Cancer. 2012;131:2710-6 pubmed publisher
    Conflicting reports exist regarding the contribution of SNP309 in MDM2 to cancer risk. Recently, SNP285 was shown to act as an antagonist to SNP309 by overriding the effect of SNP309 on SP1-mediated transcription...
  6. Piotrowski P, Lianeri M, Rubis B, Knuła H, Rybczynska M, Grodecka Gazdecka S, et al. Murine double minute clone 2,309T/G and 285G/C promoter single nucleotide polymorphism as a risk factor for breast cancer: a Polish experience. Int J Biol Markers. 2012;27:e105-10 pubmed publisher
    ..Recently, a functional polymorphism, MDM2 285G>C (rs117039649), has been discovered...
  7. Sczaniecka M, Gladstone K, Pettersson S, McLaren L, Huart A, Wallace M. MDM2 protein-mediated ubiquitination of numb protein: identification of a second physiological substrate of MDM2 that employs a dual-site docking mechanism. J Biol Chem. 2012;287:14052-68 pubmed publisher
    The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2...
  8. Yoneda T, Kuboyama A, Kato K, Ohgami T, Okamoto K, Saito T, et al. Association of MDM2 SNP309 and TP53 Arg72Pro polymorphisms with risk of endometrial cancer. Oncol Rep. 2013;30:25-34 pubmed publisher
    ..We have previously shown that the ER/MDM2/p53/p21 pathway plays an important role in endometrial carcinogenesis...
  9. Tuna G, Kucukhuseyin O, Arikan S, Kaytan Sağlam E, Guler E, Cacina C, et al. Do CDKN2 p16 540 C>G, CDKN2 p16 580 C>T, and MDM2 SNP309 T>G gene variants act on colorectal cancer development or progression?. DNA Cell Biol. 2013;32:400-8 pubmed publisher
    ..G1/S transition by regulating the p53 pathway, which was regulated by a nuclear oncoprotein, mouse double minute 2 (MDM2)...
  10. Jacob A, O BRIEN D, Singh R, Comiskey D, Littleton R, Mohammad F, et al. Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia. 2013;15:1049-63 pubmed
    ..panel of 70 RMS tumors has identified specific alternative splice variants of the oncogenes Murine Double Minute 2 (MDM2) and MDM4 as potential biomarkers for RMS...
  11. Sloan K, Bohnsack M, Watkins N. The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep. 2013;5:237-47 pubmed publisher
    ..a major consumer of cellular energy, and defects result in p53 activation via repression of mouse double minute 2 (MDM2) homolog by the ribosomal proteins RPL5 and RPL11...
  12. Kaindl U, Morak M, Portsmouth C, Mecklenbräuker A, Kauer M, Zeginigg M, et al. Blocking ETV6/RUNX1-induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia. Leukemia. 2014;28:600-8 pubmed publisher
    ..perceived p53 pathway alterations in model cell lines and primary leukemias and, in particular, how E/R upregulates MDM2, the predominant negative regulator of p53...
  13. Peng Q, Lao X, Chen Z, Lai H, Deng Y, Wang J, et al. TP53 and MDM2 gene polymorphisms, gene-gene interaction, and hepatocellular carcinoma risk: evidence from an updated meta-analysis. PLoS ONE. 2013;8:e82773 pubmed publisher
    The association between TP53 R72P and/or MDM2 SNP309 polymorphisms and hepatocellular carcinoma (HCC) risk has been widely reported, but results were inconsistent...
  14. Pan X, Li Y, Feng J, Wang X, Hao B, Shi R, et al. A functional polymorphism T309G in MDM2 gene promoter, intensified by Helicobacter pylori lipopolysaccharide, is associated with both an increased susceptibility and poor prognosis of gastric carcinoma in Chinese patients. BMC Cancer. 2013;13:126 pubmed publisher
    Studies on the association between MDM2 SNP309 (T > G) and gastric cancer have reported conflicting results...
  15. Chang Y, Graves B, Guerlavais V, Tovar C, Packman K, To K, et al. Stapled ?-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A. 2013;110:E3445-54 pubmed publisher
    ..Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo...
  16. Zheng T, Wang J, Zhao Y, Zhang C, Lin M, Wang X, et al. Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis. Nat Commun. 2013;4:2996 pubmed publisher
    ..The mechanism of mutp53 accumulation is poorly understood. Here we find that MDM2 isoforms promote mutp53 accumulation in tumours...
  17. Chen J, Zhu B, Chen J, Li Y. Genetic variations in MDM2 and P53 genes confer risk for adult acute lymphoblastic leukemia in a Chinese population. DNA Cell Biol. 2013;32:414-9 pubmed publisher
    The tumor suppressor P53 and its negative regulator mouse double minute 2 (MDM2) play crucial roles in carcinogenesis...
  18. Sparks A, Dayal S, Das J, Robertson P, Menendez S, Saville M. The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a. Oncogene. 2014;33:4685-96 pubmed publisher
    p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation...
  19. Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim Biophys Sin (Shanghai). 2014;46:180-9 pubmed publisher
    ..The levels and activity of p53 is under tight regulation to ensure its proper function. Murine double minute 2 (MDM2), a p53 target gene, is an E3 ubiquitin ligase...
  20. Zając A, Stachowiak G, Pertynski T, Romanowicz H, Wilczyński J, Smolarz B. Association between MDM2 SNP309 polymorphism and endometrial cancer risk in Polish women. Pol J Pathol. 2012;63:278-83 pubmed
    The prognostic value of the MDM2 gene amplification/expression in many types of cancer remains unclear...
  21. Nechushtan H, Hamburger T, Mendelson S, Kadouri L, Sharon N, Pikarsky E, et al. Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations. BMC Cancer. 2009;9:60 pubmed publisher
    A germ line single nucleotide polymorphism (SNP) in the first intron of the gene encoding MDM2 at position 309, an important modulator of p53, has been described...
  22. Li C, Chen L, Chen J. DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms. Mol Cell Biol. 2002;22:7562-71 pubmed
    The MDM2 homolog MDMX is an important regulator of p53 activity during embryonic development. MDMX inactivation in mice results in embryonic lethality in a p53-dependent fashion...
  23. Bothner B, Lewis W, DiGiammarino E, Weber J, Bothner S, Kriwacki R. Defining the molecular basis of Arf and Hdm2 interactions. J Mol Biol. 2001;314:263-77 pubmed
    Understanding the interaction of Arf and Hdm2 has recently become a central issue in cancer biology...
  24. Stevenson L, Sparks A, Allende Vega N, Xirodimas D, Lane D, Saville M. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007;26:976-86 pubmed
    b>Mdm2 is an E3 ubiquitin ligase that promotes its own ubiquitination and also ubiquitination of the p53 tumour suppressor...
  25. Okamoto K, Kashima K, Pereg Y, Ishida M, Yamazaki S, Nota A, et al. DNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation. Mol Cell Biol. 2005;25:9608-20 pubmed
    ..Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells...
  26. Yang Z, Zhang Y, Wang L. Mdm2 is a novel activator of ApoCIII promoter which is antagonized by p53 and SHP inhibition. Biochem Biophys Res Commun. 2012;417:744-6 pubmed publisher
    We examined the effect of Mdm2 on regulation of the ApoCIII promoter and its cross-talk with p53 and nuclear receptor SHP. Overexpression of Mdm2 markedly enhanced ApoCIII promoter activity by HNF4?...
  27. Kurki S, Peltonen K, Latonen L, Kiviharju T, Ojala P, Meek D, et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell. 2004;5:465-75 pubmed
    ..we show that NPM is a UV damage response protein that undergoes nucleoplasmic redistribution and regulates p53 and HDM2 levels and their interaction...
  28. Kulikov R, Winter M, Blattner C. Binding of p53 to the central domain of Mdm2 is regulated by phosphorylation. J Biol Chem. 2006;281:28575-83 pubmed
    The Mdm2 protein is the major regulator of the tumor suppressor protein p53. We show that the p53 protein associates both with the N-terminal and with the central domain of Mdm2...
  29. Jin A, Itahana K, O KEEFE K, Zhang Y. Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 2004;24:7669-80 pubmed
    ..Here we show that the ribosomal protein L23 interacts with HDM2. The interaction involves the central acidic domain of HDM2 and an N-terminal domain of L23...
  30. Carter S, Bischof O, Dejean A, Vousden K. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol. 2007;9:428-35 pubmed
    ..One of the most important regulators of p53 is MDM2, a RING domain E3 ligase that ubiquitinates p53, leading to both proteasomal degradation and relocation of p53 from ..
  31. Ramalingam S, Honkanen P, Young L, Shimura T, Austin J, Steeg P, et al. Quantitative assessment of the p53-Mdm2 feedback loop using protein lysate microarrays. Cancer Res. 2007;67:6247-52 pubmed
    Mathematical simulations of the p53-Mdm2 feedback loop suggest that both proteins will exhibit impulsive expression characteristics in response to high cellular stress levels...
  32. Yang Y, Xia T, Li N, Zhang J, Yang Y, Cong W, et al. Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma. Protein Cell. 2013;4:71-81 pubmed publisher
    ..Two single nucleotide polymorphisms (SNPs) in the gene loci of p53 pathway, p53 codon 72 Arg72Pro and MDM2 SNP309 (T > G), have been shown to cause perturbation of p53 function, but the effect of the two SNPs on the ..
  33. Li H, Li A, Sheppard H, Liu X. Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell. 2004;13:867-78 pubmed
    ..Significantly, the Thr-55 phosphorylation was reduced following DNA damage, suggesting that this phosphorylation contributes to the stabilization of p53 in response to DNA damage. ..
  34. Minsky N, Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol Cell. 2004;16:631-9 pubmed
    ..However, mammalian histone ubiquitylation remains poorly understood. We report that the Mdm2 oncoprotein, a RING domain E3 ubiquitin ligase known to ubiquitylate the p53 tumor suppressor protein, can interact ..
  35. Coll Mulet L, Iglesias Serret D, Santidrian A, Cosialls A, de Frias M, Castaño E, et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006;107:4109-14 pubmed
    ..Recently, nongenotoxic small-molecule activators of p53, the nutlins, have been developed that inhibit p53-MDM2 binding...
  36. Zhang J, Bai D, Ma X, Guan J, Zheng X. hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14. Oncogene. 2014;33:246-54 pubmed publisher
    The tumor-suppressor p53 provides a critical brake on tumor development. HDM2 (human double-minute 2), a p53 E3 ubiquitin ligase, is the principal cellular antagonist of p53...
  37. Kawai H, Lopez Pajares V, Kim M, Wiederschain D, Yuan Z. RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity. Cancer Res. 2007;67:6026-30 pubmed
    The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX...
  38. Forslund A, Zeng Z, Qin L, Rosenberg S, Ndubuisi M, Pincas H, et al. MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol Cancer Res. 2008;6:205-11 pubmed publisher
    b>Mdm2 is the main regulator of p53 and is amplified in approximately 7% of all human cancers. MDM2 gene amplification as well as expression has been correlated to an increased tumorigenic potential...
  39. Fang F, Yu X, Yu L, Yao L. MDM2 309 T/G polymorphism is associated with colorectal cancer risk especially in Asians: a meta-analysis. Med Oncol. 2011;28:981-5 pubmed publisher
    The murine double minute 2 (MDM2) gene encodes an important regulator which mainly functions as an E3 ligase. The role of the MDM2 protein in the P53 pathway has been especially well-studied...
  40. Caratozzolo M, Micale L, Turturo M, Cornacchia S, Fusco C, Marzano F, et al. TRIM8 modulates p53 activity to dictate cell cycle arrest. Cell Cycle. 2012;11:511-23 pubmed publisher
    ..Concurrently, TRIM8 overexpression induced the degradation of the MDM2 protein, the principal regulator of p53 stability...
  41. Gui X, Qiu L, Zhang H, Zhang D, Zhong W, Li J, et al. MDM2 309 T/G polymorphism is associated with lung cancer risk among Asians. Eur J Cancer. 2009;45:2023-6 pubmed publisher
    Published data on the association between MDM2 309 T/G polymorphism and lung cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed...
  42. Taghavi N, Biramijamal F, Sotoudeh M, Khademi H, Malekzadeh R, Moaven O, et al. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma. BMC Cancer. 2010;10:138 pubmed publisher
    Tumor suppressor genes p53 and p16INK4a and the proto-oncogene MDM2 are considered to be essential G1 cell cycle regulatory genes whose loss of function is associated with ESCC carcinogenesis...
  43. Hsieh J, Chan F, O Connor D, Mittnacht S, Zhong S, Lu X. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol Cell. 1999;3:181-93 pubmed
    The binding of RB to MDM2 is shown to be essential for RB to overcome both the antiapoptotic function of MDM2 and the MDM2-dependent degradation of p53...
  44. Midgley C, Desterro J, Saville M, Howard S, Sparks A, Hay R, et al. An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene. 2000;19:2312-23 pubmed
    The p53 tumour suppressor protein is down-regulated by the action of Mdm2, which targets p53 for rapid degradation by the ubiquitin-proteasome pathway...
  45. Gu L, Findley H, Zhou M. MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia. Blood. 2002;99:3367-75 pubmed
    b>MDM2 protein is thought to exhibit tumorigenic activity by binding to the p53 tumor-suppressor protein and inhibiting its function. Alternatively, MDM2 may have oncogenic roles other than those resulting from p53 interactions...
  46. Ohtsubo C, Shiokawa D, Kodama M, Gaiddon C, Nakagama H, Jochemsen A, et al. Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2. Cancer Sci. 2009;100:1291-9 pubmed publisher
    The mdm2 and mdmx oncogenes play essential yet nonredundant roles in synergistic inactivatiosn of p53. However, the biochemical mechanism by which Mdmx synergizes with Mdm2 to inhibit p53 function remains obscure...
  47. Shi D, Pop M, Kulikov R, Love I, Kung A, Kung A, et al. CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53. Proc Natl Acad Sci U S A. 2009;106:16275-80 pubmed publisher
  48. Marechal V, Elenbaas B, Piette J, Nicolas J, Levine A. The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes. Mol Cell Biol. 1994;14:7414-20 pubmed
  49. Arva N, Gopen T, Talbott K, Campbell L, Chicas A, White D, et al. A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J Biol Chem. 2005;280:26776-87 pubmed
    ..Impairment of the p53 pathway results in tumor cells with endogenous overexpression of Mdm2 via a naturally occurring single nucleotide polymorphism (SNP) in the mdm2 gene at position 309...
  50. Sivakolundu S, Nourse A, Moshiach S, Bothner B, Ashley C, Satumba J, et al. Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo. J Mol Biol. 2008;384:240-54 pubmed publisher
    Arf, Hdm2, and p53 regulate the tumor-suppressor pathway that is most frequently disrupted in human cancer...
  51. Yu W, Qiu Z, Gao N, Wang L, Cui H, Qian Y, et al. PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53-MDM2 loop. Nucleic Acids Res. 2011;39:2234-48 pubmed publisher
    Cell growth and proliferation are tightly controlled via the regulation of the p53-MDM2 feedback loop in response to various cellular stresses...
  52. Zhang Y, Wolf G, Bhat K, Jin A, Allio T, Burkhart W, et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol. 2003;23:8902-12 pubmed
    ..Here we report that the human homologue of MDM2, HDM2, binds to ribosomal protein L11. L11 binds a central region in HDM2 that is distinct from the ARF binding site...
  53. Sosin A, Burger A, Siddiqi A, Abrams J, Mohammad R, Al Katib A. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol. 2012;5:57 pubmed publisher
    Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity...
  54. Ranuncolo S, Varela M, Morandi A, Lastiri J, Christiansen S, Bal de Kier Joffe E, et al. Prognostic value of Mdm2, p53 and p16 in patients with astrocytomas. J Neurooncol. 2004;68:113-21 pubmed
    ..The purpose of this study was to analyze retrospectively prognostic input of p53, Mouse double minute-2 (Mdm2) and p16 in 103 uniformly treated patients with astrocytic tumors...
  55. Chen L, Gilkes D, Pan Y, Lane W, Chen J. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J. 2005;24:3411-22 pubmed
    ..Rapid activation of p53 by ionizing radiation is dependent on signaling by the ATM kinase. MDM2 and MDMX are important p53 regulators and logical targets for stress signals...
  56. Brooks C, Li M, Hu M, Shi Y, Gu W. The p53--Mdm2--HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene. 2007;26:7262-6 pubmed
    The ubiquitin-specific protease HAUSP is a critical component of the p53-Mdm2 pathway by acting as a specific deubiquitinase for both p53 and Mdm2...
  57. Ma J, Zhang J, Ning T, Chen Z, Xu C. Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma. J Hum Genet. 2012;57:261-4 pubmed publisher
    Genetic variations in MDM2, PTEN and P53 might be involved in cancer susceptibility...
  58. Miwa S, Uchida C, Kitagawa K, Hattori T, Oda T, Sugimura H, et al. Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner. Biochem Biophys Res Commun. 2006;340:54-61 pubmed
    b>Mdm2 promotes ubiquitination of the tumor suppressor p53 and can function as an oncogene by largely downregulating p53. Although a p53-independent role of Mdm2 has been reported, the underlying mechanism remains unclear...
  59. Menin C, Scaini M, De Salvo G, Biscuola M, Quaggio M, Esposito G, et al. Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst. 2006;98:285-8 pubmed
    A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T-->G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma...
  60. Lukashchuk N, Vousden K. Ubiquitination and degradation of mutant p53. Mol Cell Biol. 2007;27:8284-95 pubmed
    ..While Mdm2 can drive the degradation of both mutant and wild-type p53, our data suggest that the ability of Mdm2 to function ..
  61. Candeias M, Malbert Colas L, Powell D, Daskalogianni C, Maslon M, Naski N, et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol. 2008;10:1098-105 pubmed publisher
    The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis...
  62. Cheng T, Hsu P, Li A, Hung I, Huang M, Hsu H. Correlation of p53, MDM2 and p14(ARF) protein expression in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2009;135:1577-82 pubmed publisher
    To determine the interrelationships of p53, MDM2, and p14(ARF) protein expression in primary esophageal squamous cell carcinoma (ESCC) and their prognostic value in ESCC...
  63. Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010;285:4909-19 pubmed publisher
    ..Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation...
  64. Wang X, Wang J, Jiang X. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J Biol Chem. 2011;286:23725-34 pubmed publisher
    Genetic evidence has implicated both Mdm2 and MdmX as essential in negative regulation of p53. However, the exact role of MdmX in this Mdm2-dependent protein degradation is not well understood...
  65. Wang X, Zhang X, Qiu B, Tang Y, Sun H, Ji H, et al. MDM2 SNP309T>G polymorphism increases susceptibility to hepatitis B virus-related hepatocellular carcinoma in a northeast Han Chinese population. Liver Int. 2012;32:1172-8 pubmed publisher
    The murine double minute 2 (MDM2) gene encodes a negative regulator of the tumour protein p53...
  66. Wade M, Wang Y, Wahl G. The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol. 2010;20:299-309 pubmed publisher
    ..Critical for the control of p53 function are its two main negative regulators: Mdm2 and Mdmx...
  67. Akkiz H, Sümbül A, Bayram S, Bekar A, Akgöllü E. MDM2 promoter polymorphism is associated with increased susceptibility to hepatocellular carcinoma in Turkish population. Cancer Epidemiol. 2010;34:448-52 pubmed publisher
    The mouse double minute 2 (MDM2) gene represents one of the central nodes in the p53 pathway...
  68. Blattner C, Hay T, Meek D, Lane D. Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol. 2002;22:6170-82 pubmed
    The Mdm2 protein mediates ubiquitylation and degradation of p53 and is a key regulator of this tumor suppressor. More recently, it has been shown that Mdm2 is highly phosphorylated within its central acidic domain...
  69. Li M, Brooks C, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004;13:879-86 pubmed
    ..We further show that this phenomenon occurs because HAUSP stabilizes Mdm2 in a p53-independent manner, providing an interesting feedback loop in p53 regulation...
  70. Campbell I, Eccles D, Choong D. No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett. 2006;240:195-7 pubmed
    A functional T to G germline polymorphism in the promoter region of MDM2 (SNP309) has been reported to profoundly accelerate tumor formation suggesting that it may also represent a powerful cancer predisposing allele...
  71. Andrews P, He Y, Xiong Y. Cytoplasmic localized ubiquitin ligase cullin 7 binds to p53 and promotes cell growth by antagonizing p53 function. Oncogene. 2006;25:4534-48 pubmed
    ..CUL7 and MDM2 did not form a detectable tertiary complex with p53...
  72. Ruijs M, Schmidt M, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R, et al. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet. 2007;15:110-4 pubmed
    ..Recently, it was shown that a single-nucleotide polymorphism (SNP) in the MDM2 gene, SNP309 (T>G variation), was associated with accelerated tumour formation in LFS patients who carry a TP53 ..
  73. Jun H, Park S, Lee W, Choi J, Jang J, Kim E, et al. Combined effects of p73 and MDM2 polymorphisms on the risk of lung cancer. Mol Carcinog. 2007;46:100-5 pubmed
    ..b>MDM2 represses the transcriptional activity of p73 and thus attenuates its activity...
  74. Tang Y, Zhao W, Chen Y, Zhao Y, Gu W. Acetylation is indispensable for p53 activation. Cell. 2008;133:612-26 pubmed publisher
    ..response to genotoxic stress; however, the p53 response can only be executed if its interaction with its inhibitor Mdm2 is abolished...
  75. Chen J, Marechal V, Levine A. Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol. 1993;13:4107-14 pubmed
    ..This region contains the transactivation domain of p53, suggesting that mdm-2 may inhibit p53 function by disrupting its interaction with the general transcription machinery. ..
  76. Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000;103:321-30 pubmed
    b>Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner...
  77. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef L, Masucci M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med. 2004;10:1321-8 pubmed
    ..RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53. ..
  78. Sun X, Dai M, Lu H. 5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. J Biol Chem. 2007;282:8052-9 pubmed
    ..Here we report that 5-FU treatment leads to p53 stabilization and activation by blocking MDM2 feedback inhibition through ribosomal proteins...
  79. Chua H, Ng D, Choo S, Lum S, Li H, Soh L, et al. Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore. BMC Cancer. 2010;10:88 pubmed publisher
    Single nucleotide polymorphism (SNP) 309 resulting in a T or G allele in the promoter of MDM2, the negative regulator of p53, has been suggested to affect cancer predisposition and age of onset, primarily in females...
  80. Linares L, Scheffner M. The ubiquitin-protein ligase activity of Hdm2 is inhibited by nucleic acids. FEBS Lett. 2003;554:73-6 pubmed
    The proto-oncoprotein Hdm2 is a member of the RING finger-type family of ubiquitin-protein ligases E3...
  81. Kussie P, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine A, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996;274:948-53 pubmed
    The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription...
  82. Liu J, Zhang X, Guo Y, Sun T, Lin D, Wen T. [Genetic polymorphism in MDM2 is associated with susceptibility to colorectal cancer in a Chinese population]. Zhonghua Zhong Liu Za Zhi. 2008;30:335-8 pubmed
    ..Mouse double minute 2 (MDM2) gene is a key negative regulator of p53 pathway and overexpressed in many cancers as oncoprotein...
  83. Goldberg Z, Vogt Sionov R, Berger M, Zwang Y, Perets R, Van Etten R, et al. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J. 2002;21:3715-27 pubmed
    The p53 tumor suppressor is inhibited and destabilized by Mdm2. However, under stress conditions, this downregulation is relieved, allowing the accumulation of biologically active p53...
  84. Petenkaya A, Bozkurt B, Akilli Ozturk O, Kaya H, Gur Dedeoglu B, Yulug I. Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk. Anticancer Res. 2006;26:4975-7 pubmed
    A T-to-G polymorphism (SNP309) at the promoter region of MDM2 has been recently reported to extend the Sp1 binding site that positively regulates the MDM2 transcription level and consequently, its expression level...
  85. Yarden R, Friedman E, Metsuyanim S, Olender T, Ben Asher E, Papa M. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Breast Cancer Res Treat. 2008;111:497-504 pubmed
    A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases...
  86. Girnita L, Girnita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A. 2003;100:8247-52 pubmed
    ..This effect, which was independent of the p53 status (i.e., wild type or mutated), was prevented if Mdm2 was coinhibited...
  87. Jin Y, Lee H, Zeng S, Dai M, Lu H. MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 2003;22:6365-77 pubmed
    The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process...
  88. Meng L, Lin T, Tsai R. Nucleoplasmic mobilization of nucleostemin stabilizes MDM2 and promotes G2-M progression and cell survival. J Cell Sci. 2008;121:4037-46 pubmed publisher
    Nucleolar disassembly occurs during mitosis and nucleolar stress, releasing several MDM2-interactive proteins residing in the nucleolus that share the common activity of p53 stabilization...
  89. Nunobiki O, Ueda M, Yamamoto M, Toji E, Sato N, Izuma S, et al. Polymorphisms of p53 codon 72 and MDM2 promoter 309 and the risk of endometrial cancer. Hum Cell. 2009;22:101-6 pubmed publisher
    Genetic polymorphisms of p53 and its negative regulator murine double minute 2 homolog (MDM2) have been shown to be closely associated with tumorigenesis in a variety of human cancers...
  90. Stott F, Bates S, James M, McConnell B, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17:5001-14 pubmed
    ..the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M...
  91. Millikan R, Heard K, Winkel S, Hill E, Heard K, Massa B, et al. No association between the MDM2 -309 T/G promoter polymorphism and breast cancer in African-Americans or Whites. Cancer Epidemiol Biomarkers Prev. 2006;15:175-7 pubmed