Mdm2

Summary

Gene Symbol: Mdm2
Description: transformed mouse 3T3 cell double minute 2
Alias: 1700007J15Rik, AA415488, Mdm-2, E3 ubiquitin-protein ligase Mdm2, RING-type E3 ubiquitin transferase Mdm2, double minute 2 protein, oncoprotein Mdm2, p53-binding protein Mdm2
Species: mouse
Products:     Mdm2

Top Publications

  1. Francoz S, Froment P, Bogaerts S, De Clercq S, Maetens M, Doumont G, et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci U S A. 2006;103:3232-7 pubmed
    The Mdm2 and Mdm4 oncoproteins are key negative regulators of the p53 tumor suppressor. However, their physiological contributions to the regulation of p53 stability and activity remain highly controversial...
  2. Grier J, Xiong S, Elizondo Fraire A, Parant J, Lozano G. Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol Cell Biol. 2006;26:192-8 pubmed
    ..b>Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors...
  3. Fakharzadeh S, Trusko S, George D. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 1991;10:1565-9 pubmed
    ..The results provided evidence that a gene, mdm2, that is amplified more than 50-fold in the 3T3DM cell line, induces tumorigenicity when experimentally ..
  4. 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...
  5. Macias E, Jin A, Deisenroth C, Bhat K, Mao H, Lindström M, et al. An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction. Cancer Cell. 2010;18:231-43 pubmed publisher
    ..that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity...
  6. Lang G, Iwakuma T, Suh Y, Liu G, Rao V, Parant J, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119:861-72 pubmed
    ..These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes...
  7. Alt J, Greiner T, Cleveland J, Eischen C. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J. 2003;22:1442-50 pubmed
    b>Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2(+/-) mice has heretofore not been shown to impair tumor development...
  8. Terzian T, Dumble M, Arbab F, Thaller C, Donehower L, Lozano G, et al. Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models. J Pathol. 2011;224:540-52 pubmed publisher
    ..Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation. ..
  9. Jones S, Sands A, Hancock A, Vogel H, Donehower L, Linke S, et al. The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2. Proc Natl Acad Sci U S A. 1996;93:14106-11 pubmed
    The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression...

More Information

Publications63

  1. Valentin Vega Y, Okano H, Lozano G. The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival. Cell Death Differ. 2008;15:1772-81 pubmed publisher
    b>Mdm2 is the major inhibitor of the p53 tumor suppressor. Loss of Mdm2 in mice or in specific tissues of the mouse always yields p53-dependent lethal phenotypes. However, the role of Mdm2 in tissues with high turnover capacity is unknown...
  2. Terzian T, Suh Y, Iwakuma T, Post S, Neumann M, Lang G, et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev. 2008;22:1337-44 pubmed publisher
    ..To investigate the significance of these data, we examined the regulation of mutant p53 stability by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation, and p16INK4a, a member of the Rb tumor suppressor pathway...
  3. Boesten L, Zadelaar S, De Clercq S, Francoz S, van Nieuwkoop A, Biessen E, et al. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death. Cell Death Differ. 2006;13:2089-98 pubmed
    p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53...
  4. Terzian T, Wang Y, Van Pelt C, Box N, Travis E, Lozano G. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol Cell Biol. 2007;27:5479-85 pubmed
    ..by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4...
  5. Bouska A, Eischen C. Murine double minute 2: p53-independent roads lead to genome instability or death. Trends Biochem Sci. 2009;34:279-86 pubmed publisher
    The oncoprotein murine double minute 2 (Mdm2) is frequently overexpressed in many types of human malignancies...
  6. Momand J, Zambetti G, Olson D, George D, Levine A. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992;69:1237-45 pubmed
    ..Thus, a product of the mdm-2 oncogene forms a tight complex with the p53 protein, and the mdm-2 oncogene can inhibit p53-mediated transactivation. ..
  7. Montes de Oca Luna R, Wagner D, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995;378:203-6 pubmed
    ..The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product...
  8. Oliner J, Kinzler K, Meltzer P, George D, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992;358:80-3 pubmed
    ..b>MDM2 is a strong candidate for one such cellular protein; the MDM2 gene was originally identified by virtue of its ..
  9. Sabbatini P, McCormick F. MDMX inhibits the p300/CBP-mediated acetylation of p53. DNA Cell Biol. 2002;21:519-25 pubmed
    ..b>MDM2 inhibits the acetylation of p53 by p300/CBP through a mechanism that requires a stable p53-MDM2 interaction and ..
  10. Weber J, Kuo M, Bothner B, DiGiammarino E, Kriwacki R, Roussel M, et al. Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. Mol Cell Biol. 2000;20:2517-28 pubmed
    The ARF tumor suppressor protein stabilizes p53 by antagonizing its negative regulator, Mdm2 (Hdm2 in humans)...
  11. Momand J, Wu H, Dasgupta G. MDM2--master regulator of the p53 tumor suppressor protein. Gene. 2000;242:15-29 pubmed
    b>MDM2 is an oncogene that mainly functions to modulate p53 tumor suppressor activity...
  12. Mendrysa S, O Leary K, McElwee M, Michalowski J, Eisenman R, Powell D, et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev. 2006;20:16-21 pubmed
    The p53 inhibitor murine double-minute gene 2 (Mdm2) is a target for potential cancer therapies, however increased p53 function can be lethal...
  13. Eischen C, Alt J, Wang P. Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development. Oncogene. 2004;23:8931-40 pubmed
    The tumor suppressor p19ARF inhibits Mdm2, which restricts the activity of p53. Complicated feedback and control mechanisms regulate ARF, Mdm2, and p53 interactions...
  14. Maetens M, Doumont G, Clercq S, Francoz S, Froment P, Bellefroid E, et al. Distinct roles of Mdm2 and Mdm4 in red cell production. Blood. 2007;109:2630-3 pubmed
    b>Mdm2 and Mdm4 are critical negative regulators of the p53 tumor suppressor. Mdm4-null mutants are severely anemic and exhibit impaired proliferation of the fetal liver erythroid lineage cells...
  15. Garcia D, Warr M, Martins C, Brown Swigart L, Passegue E, Evan G. Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev. 2011;25:1746-57 pubmed publisher
    ..restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal...
  16. 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 ..
  17. Barak Y, Juven T, Haffner R, Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993;12:461-8 pubmed
    ..In the present study we show that p95 is a product of the mdm2 putative proto-oncogene. The enhanced complex formation of mdm2 with ts-p53 in cells maintained at 32...
  18. Abbas H, Maccio D, Coskun S, Jackson J, Hazen A, SILLS T, et al. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell. 2010;7:606-17 pubmed publisher
    b>Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice...
  19. Mendrysa S, McElwee M, Michalowski J, O Leary K, Young K, Perry M. mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol. 2003;23:462-72 pubmed
    ..Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival...
  20. 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...
  21. 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...
  22. Xirodimas D, Saville M, Bourdon J, Hay R, Lane D. Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell. 2004;118:83-97 pubmed
    ..Here, we show that the Mdm2 RING finger E3 ubiquitin ligase can also promote NEDD8 modification of the p53 tumor suppressor protein...
  23. Kamijo T, Weber J, Zambetti G, Zindy F, Roussel M, Sherr C. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A. 1998;95:8292-7 pubmed
    ..ARF retrovirus, we determined that mouse p19(ARF) can interact directly with p53, as well as with the p53 regulator mdm2. ARF can bind p53-DNA complexes, and it depends upon functional p53 to transcriptionally induce mdm2 and the cyclin-..
  24. Mulay S, Thomasova D, Ryu M, Anders H. MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice. Kidney Int. 2012;81:1199-211 pubmed publisher
    ..Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is under current study for cancer therapy...
  25. 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...
  26. Itahana K, Mao H, Jin A, Itahana Y, Clegg H, Lindström M, et al. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell. 2007;12:355-66 pubmed
    It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity...
  27. Singh S, Ramamoorthy M, Vaughan C, Yeudall W, Deb S, Palit Deb S. Human oncoprotein MDM2 activates the Akt signaling pathway through an interaction with the repressor element-1 silencing transcription factor conferring a survival advantage to cancer cells. Cell Death Differ. 2013;20:558-66 pubmed publisher
    ..current paradigm states that the Akt signaling pathway phosphorylates the human oncoprotein mouse double minute 2 (MDM2), leading to its nuclear translocation and degradation of the tumor suppressor p53...
  28. Doumont G, Martoriati A, Beekman C, Bogaerts S, Mee P, Bureau F, et al. G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv. EMBO J. 2005;24:3093-103 pubmed
    ..Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo. ..
  29. 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 ..
  30. Wang P, Greiner T, Lushnikova T, Eischen C. Decreased Mdm2 expression inhibits tumor development induced by loss of ARF. Oncogene. 2006;25:3708-18 pubmed
    The tumor suppressor p14/p19(ARF) regulates Mdm2, which is known for controlling the p53 tumor suppressor...
  31. Donehower L, Harvey M, Slagle B, McArthur M, Montgomery C, Butel J, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356:215-21 pubmed
  32. Hallenborg P, Feddersen S, Francoz S, Murano I, Sundekilde U, Petersen R, et al. Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation. Cell Death Differ. 2012;19:1381-9 pubmed publisher
    The role of the E3 ubiquitin ligase murine double minute 2 (Mdm2) in regulating the stability of the p53 tumor suppressor is well documented...
  33. Shvarts A, Steegenga W, Riteco N, van Laar T, Dekker P, Bazuine M, et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996;15:5349-57 pubmed
    ..This new protein has been called MDMX on the basis of its structural similarity to MDM2, which is especially notable in the p53-binding domain...
  34. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296-9 pubmed
    ..The Mdm2 oncoprotein is a potent inhibitor of p53...
  35. O Leary K, Mendrysa S, Vaccaro A, Perry M. Mdm2 regulates p53 independently of p19(ARF) in homeostatic tissues. Mol Cell Biol. 2004;24:186-91 pubmed
    ..Moreover, the Mdm2/p53/p19(ARF) pathway appears to exist only under very restricted conditions.
  36. Lin T, Chao C, Saito S, Mazur S, Murphy M, Appella E, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005;7:165-71 pubmed
    ..These findings indicate an alternative mechanism for p53 to maintain genetic stability in ESCs, by inducing the differentiation of ESCs into other cell types that undergo efficient p53-dependent cell-cycle arrest and apoptosis. ..
  37. Jones S, Roe A, Donehower L, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995;378:206-8 pubmed
    The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells...
  38. 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...
  39. Abe Y, Oda Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K, et al. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci U S A. 2008;105:4838-43 pubmed publisher
    ..We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination...
  40. Juven T, Barak Y, Zauberman A, George D, Oren M. Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene. 1993;8:3411-6 pubmed
    The p53 tumor suppressor gene product can complex with polypeptides encoded by the mdm2 putative protoncogene. In addition, mdm2 mRNA levels have been shown to increase following the activation of wild type (wt) p53...
  41. Zhang Y, Wang J, Yuan Y, Zhang W, Guan W, Wu Z, et al. Negative regulation of HDM2 to attenuate p53 degradation by ribosomal protein L26. Nucleic Acids Res. 2010;38:6544-54 pubmed publisher
    ..Overexpression of RPL26 results in activating of p53, inhibits cell proliferation and induces a p53-dependent cell cycle arrest. These results provide a novel regulatory mechanism of RPL26 to activate p53 by inhibiting HDM2. ..
  42. Girnita L, Shenoy S, Sehat B, Vasilcanu R, Girnita A, Lefkowitz R, et al. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005;280:24412-9 pubmed
    ..in the regulation of G protein-coupled receptors, serves as an adaptor to bring the oncoprotein E3 ubiquitin ligase MDM2 to the IGF-1R...
  43. Steinman H, Jones S. Generation of an Mdm2 conditional allele in mice. Genesis. 2002;32:142-4 pubmed
  44. Jones S, Hancock A, Vogel H, Donehower L, Bradley A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A. 1998;95:15608-12 pubmed
    The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers...
  45. McDonnell T, Montes de Oca Luna R, Cho S, Amelse L, Chavez Reyes A, Lozano G. Loss of one but not two mdm2 null alleles alters the tumour spectrum in p53 null mice. J Pathol. 1999;188:322-8 pubmed
    The transcriptional activity of the p53 tumour suppressor is inhibited by binding to MDM2. The in vivo significance of this interaction was established in mdm2 null mice...
  46. Parant J, Chavez Reyes A, Little N, Yan W, Reinke V, Jochemsen A, et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet. 2001;29:92-5 pubmed
    ..This protein is negatively regulated by a physical interaction with MDM2, an E3 ubiquitin ligase...
  47. Liu G, Terzian T, Xiong S, Van Pelt C, Audiffred A, Box N, et al. The p53-Mdm2 network in progenitor cell expansion during mouse postnatal development. J Pathol. 2007;213:360-8 pubmed
    b>Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality...
  48. 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 (..
  49. Hilliard S, Aboudehen K, Yao X, El Dahr S. Tight regulation of p53 activity by Mdm2 is required for ureteric bud growth and branching. Dev Biol. 2011;353:354-66 pubmed publisher
    b>Mdm2 (Murine Double Minute-2) is required to control cellular p53 activity and protein levels. Mdm2 null embryos die of p53-mediated growth arrest and apoptosis at the peri-implantation stage...
  50. Weber J, Jeffers J, Rehg J, Randle D, Lozano G, Roussel M, et al. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000;14:2358-65 pubmed
    The p19(ARF) tumor suppressor antagonizes Mdm2 to induce p53-dependent cell cycle arrest...
  51. Ringshausen I, O Shea C, Finch A, Swigart L, Evan G. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell. 2006;10:501-14 pubmed
    There is currently much interest in the idea of restoring p53 activity in tumor cells by inhibiting Hdm2/Mdm2. However, it has remained unclear whether this would also activate p53 in normal cells...
  52. Kubbutat M, Jones S, Vousden K. Regulation of p53 stability by Mdm2. Nature. 1997;387:299-303 pubmed
    ..cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein...
  53. Lim S, Chen X, Lim Y, Hanson D, Vo T, Howerton K, et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008;29:9-22 pubmed publisher
    ..FAK-/-p21-/- fibroblasts revealed that FAK, in a kinase-independent manner, facilitates p53 turnover via enhanced Mdm2-dependent p53 ubiquitination...
  54. Barak Y, Gottlieb E, Juven Gershon T, Oren M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev. 1994;8:1739-49 pubmed
    The mdm2 proto-oncogene product binds to the p53 tumor suppressor protein and inhibits its ability to trans-activate target genes...