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. 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...
  2. 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 ..
  3. 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...
  4. 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
    ..Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels...
  5. 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)...
  6. 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...
  7. 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...
  8. 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...
  9. 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...

More Information

Publications255 found, 100 shown here

  1. 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)...
  2. 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...
  3. 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...
  4. 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...
  5. 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...
  6. 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...
  7. 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...
  8. 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...
  9. 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...
  10. 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...
  11. 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...
  12. Gu L, Zhu N, Zhang H, Durden D, Feng Y, Zhou M. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell. 2009;15:363-75 pubmed publisher
    ..Herein we demonstrate that the upregulation of XIAP protein levels is regulated by MDM2 at the translational level...
  13. Gajjar M, Candeias M, Malbert Colas L, Mazars A, Fujita J, Olivares Illana V, et al. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage. Cancer Cell. 2012;21:25-35 pubmed publisher
    ..The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA...
  14. Bernardi R, Scaglioni P, Bergmann S, Horn H, Vousden K, Pandolfi P. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol. 2004;6:665-72 pubmed
    ..PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear...
  15. Coffill C, Muller P, Oh H, Neo S, Hogue K, Cheok C, et al. Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion. EMBO Rep. 2012;13:638-44 pubmed publisher
    ..Advanced proteomics has thus allowed the detection of a new mechanism of p53-driven invasion. ..
  16. Sdek P, Ying H, Zheng H, Margulis A, Tang X, Tian K, et al. The central acidic domain of MDM2 is critical in inhibition of retinoblastoma-mediated suppression of E2F and cell growth. J Biol Chem. 2004;279:53317-22 pubmed
    ..Inactivation of Rb plays a critical role in the development of human malignancies. MDM2, an oncogene frequently found amplified and overexpressed in a variety of human tumors and cancers, directly ..
  17. Wilkening S, Hemminki K, Rudnai P, Gurzau E, Koppova K, Forsti A, et al. No association between MDM2 SNP309 promoter polymorphism and basal cell carcinoma of the skin. Br J Dermatol. 2007;157:375-7 pubmed
    The MDM2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumour suppressor protein. Further, overexpression of the MDM2 gene can inhibit DNA double-strand break repair in a p53-independent manner...
  18. Bartel F, Taylor A, Taubert H, Harris L. Novel mdm2 splice variants identified in pediatric rhabdomyosarcoma tumors and cell lines. Oncol Res. 2001;12:451-7 pubmed
    b>Mdm2 is an oncogene that binds to and inactivates the tumor suppressor p53...
  19. Horn H, Vousden K. Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene. 2008;27:5774-84 pubmed publisher
    b>MDM2 is a ubiquitin ligase that plays a key role in regulating the stability of the p53 tumor suppressor protein...
  20. Markey M, Berberich S. Full-length hdmX transcripts decrease following genotoxic stress. Oncogene. 2008;27:6657-66 pubmed publisher
    ..In these studies, we report that the human mdmX (hdmX) mRNA is reproducibly decreased in various human cell lines following treatment with various DNA-damaging agents...
  21. Wang X, Arooz T, Siu W, Chiu C, Lau A, Yamashita K, et al. MDM2 and MDMX can interact differently with ARF and members of the p53 family. FEBS Lett. 2001;490:202-8 pubmed
    Members of the p53 family of transcription factors have essential roles in tumor suppression and in development. MDM2 is an essential regulator of p53 that can inhibit the transcriptional activity of p53, shuttle p53 out of the nucleus, ..
  22. Busso C, Iwakuma T, Izumi T. Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway. Oncogene. 2009;28:1616-25 pubmed publisher
    ..occurred specifically at Lys residues near the N-terminus, and was markedly enhanced by mouse double minute 2 (MDM2), the major intracellular p53 inhibitor...
  23. Okamoto K, Taya Y, Nakagama H. Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. FEBS Lett. 2009;583:2710-4 pubmed publisher
    b>mdm2 and mdmx oncogenes play essential yet non-redundant roles in synergistic inactivation of the tumor suppressor, p53...
  24. Kobet E, Zeng X, Zhu Y, Keller D, Lu H. MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A. 2000;97:12547-52 pubmed
    p300 acetylates and activates the tumor suppressor p53 after DNA damage. Here, we show that MDM2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins...
  25. Dai M, Zeng S, Jin Y, Sun X, David L, Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol. 2004;24:7654-68 pubmed
    The p53-MDM2 feedback loop is vital for cell growth control and is subjected to multiple regulations in response to various stress signals. Here we report another regulator of this loop...
  26. Sasaki M, Nie L, Maki C. MDM2 binding induces a conformational change in p53 that is opposed by heat-shock protein 90 and precedes p53 proteasomal degradation. J Biol Chem. 2007;282:14626-34 pubmed
    ..degradation was blocked during recovery from stress treatment and in cells co-expressing p53 and MDM2. This suggests that conformational change precedes wild-type p53 degradation by the proteasome...
  27. De Nicola F, Bruno T, Iezzi S, Di Padova M, Floridi A, Passananti C, et al. The prolyl isomerase Pin1 affects Che-1 stability in response to apoptotic DNA damage. J Biol Chem. 2007;282:19685-91 pubmed
    ..with the peptidyl-prolyl isomerase Pin1 and that conformational changes generated by Pin1 are required for Che-1/HDM2 interaction...
  28. Weaver J, Downs Kelly E, Goldblum J, Turner S, Kulkarni S, Tubbs R, et al. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol. 2008;21:943-9 pubmed publisher
    ..Cytogenetics in these tumors has identified ring and giant chromosomes composed of 12q13-15 amplicons including the MDM2 gene...
  29. Czarna A, Popowicz G, Pecak A, Wolf S, Dubin G, Holak T. High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx. Cell Cycle. 2009;8:1176-84 pubmed
    The Mdm2 and Mdmx proteins are the principal negative regulators of the p53 tumor suppressor. Reactivation of p53 activity by disrupting the Mdm2/Mdmx-p53 interactions offers new possibilities for anticancer therapeutics...
  30. Shenoy S, Modi A, Shukla A, Xiao K, Berthouze M, Ahn S, et al. Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A. 2009;106:6650-5 pubmed publisher
    ..Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization...
  31. Lukas J, Gao D, Keshmeshian M, Wen W, Tsao Wei D, Rosenberg S, et al. Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res. 2001;61:3212-9 pubmed
    b>mdm2 is part of a complex mechanism that regulates the expression of p53 as well as the function of Rb, p19ARF, and other genes. In humans, mdm2 dysregulation is associated with gene amplification...
  32. Bartel F, Taubert H, Harris L. Alternative and aberrant splicing of MDM2 mRNA in human cancer. Cancer Cell. 2002;2:9-15 pubmed
    b>MDM2 has been characterized as a protein that binds to and facilitates degradation of the tumor suppressor p53...
  33. Wang P, Wu Y, Ge X, Ma L, Pei G. Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J Biol Chem. 2003;278:11648-53 pubmed
    ..although both beta-arrestin1 and beta-arrestin2 are able to interact with ubiquitin-protein isopeptide ligase (E3) Mdm2, only expression of beta-arrestin2 leads to the relocalization of Mdm2 from the nucleus to the cytoplasm...
  34. Bartel F, Harris L, Wurl P, Taubert H. MDM2 and its splice variant messenger RNAs: expression in tumors and down-regulation using antisense oligonucleotides. Mol Cancer Res. 2004;2:29-35 pubmed
    ..An example of a gene with more than one transcript is the MDM2 oncogene. To date, more than 40 different splice variants have been isolated from both tumor and normal tissues...
  35. Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo Y, et al. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 2005;8:75-87 pubmed
    ..In vitro and in vivo experiments revealed that gankyrin binds to Mdm2, facilitating p53-Mdm2 binding, and increases ubiquitylation and degradation of p53...
  36. Fuchs S, Adler V, Buschmann T, Wu X, Ronai Z. Mdm2 association with p53 targets its ubiquitination. Oncogene. 1998;17:2543-7 pubmed
    ..In the present study we have elucidated the mechanism by which Mdm2 regulates p53 degradation...
  37. Sharp D, Kratowicz S, Sank M, George D. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem. 1999;274:38189-96 pubmed
    The MDM2 oncoprotein has transforming potential that can be activated by overexpression, and it represents a critical regulator of the p53 tumor suppressor protein...
  38. Kurki S, Latonen L, Laiho M. Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization. J Cell Sci. 2003;116:3917-25 pubmed
    b>Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins...
  39. Li D, Marchenko N, Schulz R, Fischer V, Velasco Hernandez T, Talos F, et al. Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells. Mol Cancer Res. 2011;9:577-88 pubmed publisher
    The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors...
  40. Bartel F, Meye A, Wurl P, Kappler M, Bache M, Lautenschlager C, et al. Amplification of the MDM2 gene, but not expression of splice variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma. Int J Cancer. 2001;95:168-75 pubmed
    The MDM2 gene encodes a 90-kDa oncoprotein that is overexpressed in several human carcinomas, osteosarcomas, gliomas and soft tissue sarcomas (STSs)...
  41. Shenoy S, McDonald P, Kohout T, Lefkowitz R. Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science. 2001;294:1307-13 pubmed
    ..Receptor ubiquitination required beta-arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of beta-arrestin ubiquitination, either by expression in Mdm2-null cells or by dominant-negative forms ..
  42. Wang P, Gao H, Ni Y, Wang B, Wu Y, Ji L, et al. Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2. J Biol Chem. 2003;278:6363-70 pubmed
    b>Oncoprotein Mdm2 is a master negative regulator of the tumor suppressor p53 and has been recently shown to regulate the ubiquitination of beta-arrestin 2, an important adapter and scaffold in signaling of G-protein-coupled receptors (..
  43. Badciong J, Haas A. MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination. J Biol Chem. 2002;277:49668-75 pubmed
    It has been well documented that Mdm2 and its homologue MdmX not only are critical negative regulators of the tumor suppressor p53 but that both Mdm2 and MdmX interact to affect the function of the other...
  44. Kinyamu H, Archer T. Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cell Biol. 2003;23:5867-81 pubmed
    ..this, we demonstrate that E2-mediated GR degradation is coupled to an increase in p53 and its key regulator protein Mdm2 (murine double minute 2), an E3 ubiquitin ligase shown to target the GR for degradation...
  45. Chen Y, Chang Y, Chang J, Wu S. Genotyping of single nucleotide polymorphism in MDM2 genes by universal fluorescence primer PCR and capillary electrophoresis. Anal Bioanal Chem. 2009;394:1291-7 pubmed publisher
    Single nucleotide polymorphism (SNP) 309 in the promoter region of the murine double minute 2 (MDM2) gene plays an important role in human tumorigenesis. We established a simple and effective CE method for SNP detection in the MDM2 gene...
  46. Dimitriadi M, Poulogiannis G, Liu L, Bäcklund L, Pearson D, Ichimura K, et al. p53-independent mechanisms regulate the P2-MDM2 promoter in adult astrocytic tumours. Br J Cancer. 2008;99:1144-52 pubmed publisher
    The MDM2 gene is amplified and/or overexpressed in about 10% of glioblastomas and constitutes one of a number of ways the p53 pathway is disrupted in these tumours...
  47. Wang X, Yang J, Ho B, Yang Y, Huang Z, Zhang Z, et al. Interaction of Helicobacter pylori with genetic variants in the MDM2 promoter, is associated with gastric cancer susceptibility in Chinese patients. Helicobacter. 2009;14:114-9 pubmed publisher
    b>MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 ..
  48. Zdzalik M, Pustelny K, Kedracka Krok S, Huben K, Pecak A, Wladyka B, et al. Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73. Cell Cycle. 2010;9:4584-91 pubmed
    The negative regulation of p53, a major human tumor suppressor, by Mdm2 and Mdmx is crucial for the survival of a cell, whereas its aberrant function is a common feature of cancer...
  49. Hwang Y, Lu T, Huang D, Kuo Y, Kao C, Yeh N, et al. NOLC1, an enhancer of nasopharyngeal carcinoma progression, is essential for TP53 to regulate MDM2 expression. Am J Pathol. 2009;175:342-54 pubmed publisher
    ..Measuring the expression levels of genes related to cell growth, apoptosis, and angiogenesis, we found that the MDM2 gene was down-regulated in the transfectants...
  50. Liu G, Jiang D, Shen S, Yu L. MDM2 SNP309T>G polymorphism with hepatocellular carcinoma risk: a meta-analysis. Arch Med Res. 2011;42:149-55 pubmed publisher
    The murine double minute 2 (MDM2) gene encodes a negative regulator of the tumor protein p53...
  51. 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...
  52. Weber H, Ludwig R, Morrison D, Kotlyarov A, Gaestel M, Vousden K. HDM2 phosphorylation by MAPKAP kinase 2. Oncogene. 2005;24:1965-72 pubmed
    ..acid renders HDM2 slightly more active in the degradation of p53, and mouse cells deficient for MK2 show reduced Mdm2 phosphorylation and elevated levels of p53 protein...
  53. Zhu H, Wu L, Maki C. MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53. J Biol Chem. 2003;278:49286-92 pubmed
    ..b>MDM2 binding inhibits p53 and promotes its degradation by the proteasome, whereas promyelocytic leukemia (PML) activates ..
  54. Paulin F, O Neill M, McGregor G, Cassidy A, Ashfield A, Ali C, et al. MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism. BMC Cancer. 2008;8:281 pubmed publisher
    A functional polymorphism within MDM2, SNP309 T>G, has been linked to early onset cancer...
  55. Kang H, Feng Z, Sun Y, Atwal G, Murphy M, Rebbeck T, et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci U S A. 2009;106:9761-6 pubmed publisher
    ..Selected alleles in SNPs in LIF, Mdm2, Mdm4, and Hausp genes, each of which regulates p53 levels in cells, are also enriched in IVF patients...
  56. Yu G, Rudiger S, Veprintsev D, Freund S, Fernandez Fernandez M, Fersht A. The central region of HDM2 provides a second binding site for p53. Proc Natl Acad Sci U S A. 2006;103:1227-32 pubmed
    b>HDM2 is a negative regulator of p53 that inhibits its transcriptional activity and subjects it to degradation by an E3 ligase activity. The primary binding site for HDM2 on p53 is located in its N-terminal domain...
  57. Bond G, Menin C, Bertorelle R, Alhopuro P, Aaltonen L, Levine A. MDM2 SNP309 accelerates colorectal tumour formation in women. J Med Genet. 2006;43:950-2 pubmed
    Recent studies have shown that the G-allele of MDM2 SNP309 (T/G) in the p53 tumour suppressor pathway can accelerate tumorigenesis and alter the risk of various cancers in women and not in men...
  58. Singh R, Iyappan S, Scheffner M. Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2. J Biol Chem. 2007;282:10901-7 pubmed
    b>Mdm2 is a member of the RING finger family of ubiquitin ligases and is best known for its role in targeting the tumor suppressor p53 for ubiquitination and degradation...
  59. Joshi A, Budhathoki S, Ohnaka K, Mibu R, Tanaka M, Kakeji Y, et al. TP53 R72P and MDM2 SNP309 polymorphisms and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. Jpn J Clin Oncol. 2011;41:232-8 pubmed publisher
    ..67 (95% confidence interval, 1.11-2.51). Codon 72 polymorphism of p53 and SNP309 in combination may confer an increased risk of colorectal cancer. ..
  60. Joo H, Kim J, Jeong J, Seong K, Nam S, Yang K, et al. Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of AKT and MDM2. Eur J Cell Biol. 2011;90:420-31 pubmed publisher
    ..Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT...
  61. Matsumoto R, Tada M, Nozaki M, Zhang C, Sawamura Y, Abe H. Short alternative splice transcripts of the mdm2 oncogene correlate to malignancy in human astrocytic neoplasms. Cancer Res. 1998;58:609-13 pubmed
    The mdm2 oncogene encodes a 90-kDa nuclear phosphoprotein that binds and inhibits the function of the p53 tumor suppressor protein...
  62. Jin Y, Zeng S, Lee H, Lu H. MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation. J Biol Chem. 2004;279:20035-43 pubmed
    We recently reported that MDM2, a negative feedback regulator of the tumor suppressor p53, inhibits p300/CREB-binding protein-associated factor (PCAF)-mediated p53 acetylation...
  63. Sui G, Affar E, Shi Y, Brignone C, Wall N, Yin P, et al. Yin Yang 1 is a negative regulator of p53. Cell. 2004;117:859-72 pubmed
    ..Significantly, recombinant YY1 is sufficient to induce Hdm2-mediated p53 polyubiquitination in vitro, suggesting that this function of YY1 is independent of its ..
  64. Sanchez Carbayo M, Socci N, Kirchoff T, Erill N, Offit K, Bochner B, et al. A polymorphism in HDM2 (SNP309) associates with early onset in superficial tumors, TP53 mutations, and poor outcome in invasive bladder cancer. Clin Cancer Res. 2007;13:3215-20 pubmed
    The HDM2 gene represents one of the central nodes in the p53 pathway...
  65. Dayal S, Sparks A, Jacob J, Allende Vega N, Lane D, Saville M. Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. J Biol Chem. 2009;284:5030-41 pubmed publisher
    Both p53 and its repressor Mdm2 are subject to ubiquitination and proteasomal degradation. We show that knockdown of the deubiquitinating enzyme USP5 (isopeptidase T) results in an increase in the level and transcriptional activity of p53...
  66. Cao X, Zhang T, Zhao Z, Zhao T. MDM2 SNP309 polymorphism and colorectal cancer risk: a meta-analysis. DNA Cell Biol. 2012;31:355-9 pubmed publisher
    b>MDM2 is a phosphoprotein that interacts with p53 and inhibits its activity...
  67. Knappskog S, Gansmo L, Romundstad P, Bjørnslett M, Trovik J, Sommerfelt Pettersen J, et al. MDM2 promoter SNP344T>A (rs1196333) status does not affect cancer risk. PLoS ONE. 2012;7:e36263 pubmed publisher
    The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas...
  68. Boersma B, Howe T, Goodman J, Yfantis H, Lee D, Chanock S, et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst. 2006;98:911-9 pubmed
    A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor ..
  69. Phelps M, Darley M, Primrose J, Blaydes J. p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Res. 2003;63:2616-23 pubmed
    ..Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-..
  70. Jin Y, Zeng S, Sun X, Lee H, Blattner C, Xiao Z, et al. MDMX promotes proteasomal turnover of p21 at G1 and early S phases independently of, but in cooperation with, MDM2. Mol Cell Biol. 2008;28:1218-29 pubmed
    We have shown previously that MDM2 promotes the degradation of the cyclin-dependent kinase inhibitor p21 through a ubiquitin-independent proteolytic pathway. Here we report that the MDM2 analog, MDMX, also displays a similar activity...
  71. Shimizu H, Burch L, Smith A, Dornan D, Wallace M, Ball K, et al. The conformationally flexible S9-S10 linker region in the core domain of p53 contains a novel MDM2 binding site whose mutation increases ubiquitination of p53 in vivo. J Biol Chem. 2002;277:28446-58 pubmed
    Although the N-terminal BOX-I domain of the tumor suppressor protein p53 contains the primary docking site for MDM2, previous studies demonstrated that RNA stabilizes the MDM2.p53 complex using a p53 mutant lacking the BOX-I motif...
  72. Hu Z, Ma H, Lu D, Qian J, Zhou J, Chen Y, et al. Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population. Int J Cancer. 2006;118:1275-8 pubmed
    Overexpression of MDM2 may attenuate the P53 stress response pathway through direct blocking of P53 transcriptional activity and mediating P53 degradation...
  73. Ohmiya N, Taguchi A, Mabuchi N, Itoh A, Hirooka Y, Niwa Y, et al. MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. J Clin Oncol. 2006;24:4434-40 pubmed
    Recently, a single-nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to lower the age of onset of tumors and increase the occurrence of multiple primary tumors in Li-Fraumeni syndrome, and accelerate the development of ..
  74. Kass E, Poyurovsky M, Zhu Y, Prives C. Mdm2 and PCAF increase Chk2 ubiquitination and degradation independently of their intrinsic E3 ligase activities. Cell Cycle. 2009;8:430-7 pubmed
    ..1) Here we show that the S456A mutant preferentially binds to Mdm2 compared to wild-type Chk2 and downregulation of Mdm2 with siRNA can rescue the observed destabilization of S456A ..
  75. Li M, Gu W. A critical role for noncoding 5S rRNA in regulating Mdmx stability. Mol Cell. 2011;43:1023-32 pubmed publisher
    Both p53 and Mdmx are ubiquitinated and degraded by the same E3 ligase Mdm2; interestingly, however, while p53 is rapidly degraded by Mdm2, Mdmx is a stable protein in most cancer cells...
  76. Dastidar S, Raghunathan D, Nicholson J, Hupp T, Lane D, Verma C. Chemical states of the N-terminal "lid" of MDM2 regulate p53 binding: simulations reveal complexities of modulation. Cell Cycle. 2011;10:82-9 pubmed
    Phosphorylation of S17 in the N-terminal "lid" of MDM2 (residues 1-24) is proposed to regulate the binding of p53...
  77. Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M. MDM2 interacts with MDMX through their RING finger domains. FEBS Lett. 1999;447:5-9 pubmed
    The N-terminus of MDM2 proto-oncoprotein interacts with p53 and down modulates p53 activity by inhibiting transcriptional activity and promoting p53 degradation. MDMX is structurally related to MDM2 and also binds to p53...
  78. Zhang Y, Xiong Y. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol Cell. 1999;3:579-91 pubmed
    ..the nucleolus via a sequence within the exon 2-encoded C-terminal domain and is induced to leave the nucleolus by MDM2. ARF forms nuclear bodies with MDM2 and p53 and blocks p53 and MDM2 nuclear export...
  79. Clark P, Llanos S, Peters G. Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2. Oncogene. 2002;21:4498-507 pubmed
    ..basic protein p14ARF, encoded by one of the alternative transcripts from the human INK4A/ARF locus, interferes with MDM2-mediated ubiquitination of the p53 tumour suppressor protein...
  80. Dai M, Shi D, Jin Y, Sun X, Zhang Y, Grossman S, et al. Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J Biol Chem. 2006;281:24304-13 pubmed
    Inhibition of the MDM2-p53 feedback loop is critical for p53 activation in response to cellular stresses...
  81. Bouska A, Lushnikova T, Plaza S, Eischen C. Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol. 2008;28:4862-74 pubmed publisher
    b>Mdm2, a regulator of the tumor suppressor p53, is frequently overexpressed in human malignancies. Mdm2 also has unresolved, p53-independent functions that contribute to tumorigenesis...
  82. Cheng T, Cohen S. Human MDM2 isoforms translated differentially on constitutive versus p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feedback control loops. Mol Cell Biol. 2007;27:111-9 pubmed
    Proteins encoded by the mdm2 gene, which has a pivotal role in the regulation of growth and differentiation, exist principally in human and murine cells as two isoforms that migrate in gels as 75-kDa and 90-kDa proteins...
  83. Galli F, Rossi M, D Alessandra Y, De Simone M, Lopardo T, Haupt Y, et al. MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation. J Cell Sci. 2010;123:2423-33 pubmed publisher
    ..Here, we describe a new regulatory pathway for the DeltaNp63alpha protein. We found that MDM2 binds DeltaNp63alpha in the nucleus promoting its translocation to the cytoplasm...
  84. Stad R, Little N, Xirodimas D, Frenk R, van der Eb A, Lane D, et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep. 2001;2:1029-34 pubmed
    ..regulation of p53 activity occurs at the level of protein stability, largely determined by the activity of the Mdm2 protein...
  85. Tsuiki H, Nishi T, Takeshima H, Yano S, Nakamura H, Makino K, et al. Single nucleotide polymorphism 309 affects murin-double-minute 2 protein expression but not glioma tumorigenesis. Neurol Med Chir (Tokyo). 2007;47:203-8; discussion 208-9 pubmed
    Murin-double-minute 2 (MDM2) is an important negative regulator of the p53 tumor suppressor, and affects the p53 protein level and transcriptional activity...
  86. Mayo L, Seo Y, Jackson M, Smith M, Rivera Guzman J, Korgaonkar C, et al. Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified. J Biol Chem. 2005;280:25953-9 pubmed
    ..We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to ..
  87. Lindström M, Jin A, Deisenroth C, White Wolf G, Zhang Y. Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation. Mol Cell Biol. 2007;27:1056-68 pubmed
    The p53-inhibitory function of the oncoprotein MDM2 is regulated by a number of MDM2-binding proteins, including ARF and ribosomal proteins L5, L11, and L23, which bind the central acidic domain of MDM2 and inhibit its E3 ubiquitin ligase ..
  88. Ofir Rosenfeld Y, Boggs K, Michael D, Kastan M, Oren M. Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Mol Cell. 2008;32:180-9 pubmed publisher
    b>Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells...
  89. 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...