Mdm4

Summary

Gene Symbol: Mdm4
Description: transformed mouse 3T3 cell double minute 4
Alias: 4933417N07Rik, AA414968, AL023055, AU018793, AU021806, C85810, Mdmx, protein Mdm4, double minute 4 protein, mdm2-like p53-binding protein, p53-binding protein Mdm4, protein Mdmx
Species: mouse
Products:     Mdm4

Top Publications

  1. Rallapalli R, Strachan G, Cho B, Mercer W, Hall D. A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity. J Biol Chem. 1999;274:8299-308 pubmed
    The MDMX gene product is related to the MDM2 oncoprotein, both of which interact with the p53 tumor suppressor...
  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
    ..Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors...
  3. Pant V, Xiong S, Iwakuma T, Quintas Cardama A, Lozano G. Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc Natl Acad Sci U S A. 2011;108:11995-2000 pubmed publisher
    Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation...
  4. Steinman H, Sluss H, Sands A, Pihan G, Jones S. Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth. Oncogene. 2004;23:303-6 pubmed
    b>Mdm4 (MdmX) is a p53-binding protein that shares structural similarities with Mdm2 and has been proposed to be a negative regulator of p53 function...
  5. Finch R, Donoviel D, Potter D, Shi M, Fan A, Freed D, et al. mdmx is a negative regulator of p53 activity in vivo. Cancer Res. 2002;62:3221-5 pubmed
    ..Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the ..
  6. Xiong S, Pant V, Suh Y, Van Pelt C, Wang Y, Valentin Vega Y, et al. Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res. 2010;70:7148-54 pubmed publisher
    High levels of the critical p53 inhibitor Mdm4 is common in tumors that retain a wild-type p53 allele, suggesting that Mdm4 overexpression is an important mechanism for p53 inactivation during tumorigenesis...
  7. Mancini F, Di Conza G, Pellegrino M, Rinaldo C, Prodosmo A, Giglio S, et al. MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. EMBO J. 2009;28:1926-39 pubmed publisher
    b>MDM4 is a key regulator of p53, whose biological activities depend on both transcriptional activity and transcription-independent mitochondrial functions...
  8. Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R, et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol. 2004;24:5835-43 pubmed
    ..A role for Mdmx (or Mdm4) as a key negative regulator of p53 function in vivo has been established...
  9. 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...

More Information

Publications79

  1. 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
    MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers...
  2. Pant V, Xiong S, Jackson J, Post S, Abbas H, Quintas Cardama A, et al. The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Genes Dev. 2013;27:1857-67 pubmed publisher
    ..Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies. ..
  3. Phillips A, Teunisse A, Lam S, Lodder K, Darley M, Emaduddin M, et al. HDMX-L is expressed from a functional p53-responsive promoter in the first intron of the HDMX gene and participates in an autoregulatory feedback loop to control p53 activity. J Biol Chem. 2010;285:29111-27 pubmed publisher
  4. Wang Y, Leblanc M, Wade M, Jochemsen A, Wahl G. Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases. Cancer Cell. 2009;16:33-43 pubmed publisher
    b>Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation...
  5. Xiong S, Van Pelt C, Elizondo Fraire A, Liu G, Lozano G. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc Natl Acad Sci U S A. 2006;103:3226-31 pubmed
    Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent...
  6. 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
    ..domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect ..
  7. De Clercq S, Gembarska A, Denecker G, Maetens M, Naessens M, Haigh K, et al. Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. Mol Cell Biol. 2010;30:5394-405 pubmed publisher
    Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function...
  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. Toledo F, Wahl G. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909-23 pubmed
    ..tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest...
  10. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang Z, et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A. 2011;108:12001-6 pubmed publisher
    There are currently two distinct models proposed to explain why both MDM2 and MDMX are required in p53 control, with a key difference centered on whether these two p53 inhibitors work together or independently...
  11. Xiong S, Van Pelt C, Elizondo Fraire A, Fernandez Garcia B, Lozano G. Loss of Mdm4 results in p53-dependent dilated cardiomyopathy. Circulation. 2007;115:2925-30 pubmed
    ..Mdm2, a p53-negative regulator, protects cardiomyocytes from ischemic and reperfusion-induced cell death. Mdm4, a homolog of Mdm2, inhibits p53 activity in numerous cell types...
  12. 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
    ..mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo-lethal phenotypes that are completely rescued by concomitant deletion of ..
  13. 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...
  14. Marine J, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006;13:927-34 pubmed
  15. Meulmeester E, Maurice M, Boutell C, Teunisse A, Ovaa H, Abraham T, et al. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell. 2005;18:565-76 pubmed
    ..Importantly, impaired deubiquitination of Hdmx/Hdm2 by HAUSP contributes to the DNA damage-induced degradation of Hdmx and transient instability of Hdm2. ..
  16. Matijasevic Z, Steinman H, Hoover K, Jones S. MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice. Mol Cell Biol. 2008;28:1265-73 pubmed
    Mdm2 and MdmX are structurally related p53-binding proteins that function as critical negative regulators of p53 activity in embryonic and adult tissue...
  17. Bezzi M, Teo S, Müller J, Mok W, Sahu S, Vardy L, et al. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 2013;27:1903-16 pubmed publisher
    ..We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to ..
  18. 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
    Here we report the isolation of a cDNA encoding a new p53-associating protein. 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...
  19. Migliorini D, Lazzerini Denchi E, Danovi D, Jochemsen A, Capillo M, Gobbi A, et al. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol. 2002;22:5527-38 pubmed
    We report here the characterization of a mutant mouse line with a specific gene trap event in the Mdm4 locus. Absence of Mdm4 expression results in embryonic lethality (10...
  20. Chandler D, Singh R, Caldwell L, Bitler J, Lozano G. Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. Cancer Res. 2006;66:9502-8 pubmed
    ..The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53...
  21. 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
    ..The recently discovered MDM2-related protein MDM4 (also known as MDMX) has some of the same properties as MDM2...
  22. Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, Jochemsen A, et al. Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem. 2002;277:19251-4 pubmed
    b>MDMX, an MDM2-related protein, has emerged as yet another essential negative regulator of p53 tumor suppressor, since loss of MDMX expression results in p53-dependent embryonic lethality in mice...
  23. Parant J, Reinke V, Mims B, Lozano G. Organization, expression, and localization of the murine mdmx gene and pseudogene. Gene. 2001;270:277-83 pubmed
    The mdmx gene is the first additional member of the mdm2 gene family to be isolated. It encodes a protein similar to MDM2 in several domains and also retains the ability to bind and inhibit p53 transactivation in vitro...
  24. Lee J, Jin Y, He G, Zeng S, Wang Y, Wahl G, et al. Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and consequent 14-3-3? inactivation of MDMX protein. J Biol Chem. 2012;287:20898-903 pubmed publisher
    ..Here, we showed that hypoxia could induce phosphorylation of MDMX at Ser-367 and enhance the binding of this phosphorylated MDMX to 14-3-3?, consequently leading to p53 activation...
  25. Yao R, Wang Y, You M. Chromosome mapping and sequence variation of the murine Ras effector gene Nore1. Cytogenet Cell Genet. 2001;95:126-8 pubmed
  26. Toledo F, Krummel K, Lee C, Liu C, Rodewald L, Tang M, et al. A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. Cancer Cell. 2006;9:273-85 pubmed
    The mechanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53DeltaP)...
  27. Colacurcio D, Zyskind J, Jordan Sciutto K, Espinoza C. Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid β-induced neuronal damage. Neurosci Lett. 2015;609:182-8 pubmed publisher
    MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells...
  28. Kim S, Günesdogan U, Zylicz J, Hackett J, Cougot D, Bao S, et al. PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos. Mol Cell. 2014;56:564-79 pubmed publisher
    ..Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation. ..
  29. Vuong L, Brobst D, Saadi A, Ivanovic I, Al Ubaidi M. Pattern of expression of p53, its family members, and regulators during early ocular development and in the post-mitotic retina. Invest Ophthalmol Vis Sci. 2012;53:4821-31 pubmed publisher
    ..Expression patterns of p63, p73, Mdm2, Mdm4, and Yy1 did not follow that of p53...
  30. Gannon H, Jones S. Using Mouse Models to Explore MDM-p53 Signaling in Development, Cell Growth, and Tumorigenesis. Genes Cancer. 2012;3:209-18 pubmed publisher
    ..This requisite inhibition of p53 is performed primarily by the MDM oncoproteins, Mdm2 and MdmX. These p53-binding proteins limit p53 activity both in normal cells and in stressed cells seeking to promote ..
  31. Carrillo A, Bouska A, Arrate M, Eischen C. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene. 2015;34:846-56 pubmed publisher
    The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor...
  32. Zhang G, Xie Y, Zhou Y, Xiang C, Chen L, Zhang C, et al. p53 pathway is involved in cell competition during mouse embryogenesis. Proc Natl Acad Sci U S A. 2017;114:498-503 pubmed publisher
    ..Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53...
  33. Livera G, Uzbekov R, Jarrier P, Fouchécourt S, Duquenne C, Parent A, et al. Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53-dependent and results in female sterility. FEBS Lett. 2016;590:2566-74 pubmed publisher
    Murine double minute 2 and 4 (Mdm2, Mdm4) are major p53-negative regulators, preventing thus uncontrolled apoptosis induction in numerous cell types, although their function in the female germ line has received little attention...
  34. Tashakori M, Zhang Y, Xiong S, You M, Lozano G. p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis. Mol Cancer Res. 2016;14:56-65 pubmed publisher
    b>Mdm4 negatively regulates the p53 tumor suppressor. Mdm4 loss in mice leads to an embryonic lethal phenotype that is p53-dependent...
  35. Mancini F, Di Conza G, Monti O, Macchiarulo A, Pellicciari R, Pontecorvi A, et al. Puzzling over MDM4-p53 network. Int J Biochem Cell Biol. 2010;42:1080-3 pubmed publisher
    MDM4 (also called MDMX) has been initially identified as p53 inhibitor. Subsequent data have reinforced this role pointing to the requirement for MDM4 repressive activity on p53 for mouse embryo development...
  36. Tollini L, Jin A, Park J, Zhang Y. Regulation of p53 by Mdm2 E3 ligase function is dispensable in embryogenesis and development, but essential in response to DNA damage. Cancer Cell. 2014;26:235-47 pubmed publisher
    ..mouse; Mdm2(Y487A) mutation inactivates Mdm2 E3 ligase function without affecting its ability to bind its homolog MdmX. Unexpectedly, Mdm2(Y487A/Y487A) mice were viable and developed normally into adulthood...
  37. Joshi Y, Sória M, Quadrato G, Inak G, Zhou L, Hervera A, et al. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain. 2015;138:1843-62 pubmed publisher
    ..ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the ..
  38. Carr M, Roderick J, Gannon H, Kelliher M, Jones S. Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis. Cell Rep. 2016;16:2618-2629 pubmed publisher
  39. Iyappan S, Wollscheid H, Rojas Fernandez A, Marquardt A, Tang H, Singh R, et al. Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. J Biol Chem. 2010;285:33065-72 pubmed publisher
    The related RING domain proteins MdmX and Mdm2 are best known for their role as negative regulators of the tumor suppressor p53...
  40. Tollini L, Zhang Y. p53 Regulation Goes Live-Mdm2 and MdmX Co-Star: Lessons Learned from Mouse Modeling. Genes Cancer. 2012;3:219-25 pubmed publisher
    ..The homologous proteins Mdm2 and MdmX function as the primary negative regulators of p53 stability and activity...
  41. Wang C, Wang J, Liu Z, Ma X, Wang X, Jin H, et al. Ubiquitin-specific protease 2a stabilizes MDM4 and facilitates the p53-mediated intrinsic apoptotic pathway in glioblastoma. Carcinogenesis. 2014;35:1500-9 pubmed publisher
    The mouse double minute 4 (MDM4) oncoprotein may inhibit tumorigenesis by regulating the apoptotic mediator p53...
  42. Fan C, Wang X. Mdm2 Splice isoforms regulate the p53/Mdm2/Mdm4 regulatory circuit via RING domain-mediated ubiquitination of p53 and Mdm4. Cell Cycle. 2017;16:660-664 pubmed publisher
    p53 is regulated by heterodimer E3 ligase Mdm2-Mdm4 via RING domain interaction. Mdm2 transcripts undergo alternative splicing, and Mdm2 splice isoforms are increased in cancer and induced by DNA damage...
  43. Gembarska A, Luciani F, Fedele C, Russell E, Dewaele M, Villar S, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18:1239-47 pubmed publisher
    ..Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼..
  44. Iwakuma T, Parant J, Fasulo M, Zwart E, Jacks T, de Vries A, et al. Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice. Oncogene. 2004;23:7644-50 pubmed
    Mdm2 and its homolog Mdm4 inhibit the function of the tumor suppressor p53...
  45. Clegg H, Itahana Y, Itahana K, Ramalingam S, Zhang Y. Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction. PLoS ONE. 2012;7:e38212 pubmed publisher
    ..and the acetyltransferase CBP/p300, and it fails to heterodimerize with its homolog and sister regulator of p53, Mdmx, suggesting that a fully intact RING domain is required for Mdm2's inhibition of the p300-p53 interaction and for ..
  46. Chavez Reyes A, Parant J, Amelse L, de Oca Luna R, Korsmeyer S, Lozano G. Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets. Cancer Res. 2003;63:8664-9 pubmed
    ..Deletion of either mdm2 or mdm4 genes, which encode p53 inhibitors, results in embryonic lethality...
  47. Marine J, Jochemsen A. Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun. 2005;331:750-60 pubmed
    ..10 years ago, a search for new p53-interactors revealed the existence of an Mdm2-structurally related protein, Mdmx (or Mdm4)...
  48. Benosman S, Gross I, Clarke N, Jochemsen A, Okamoto K, Loeffler J, et al. Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis. Cell Death Differ. 2007;14:2047-57 pubmed
    b>MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death...
  49. Simeonova I, Jaber S, Draskovic I, Bardot B, Fang M, Bouarich Bourimi R, et al. Mutant mice lacking the p53 C-terminal domain model telomere syndromes. Cell Rep. 2013;3:2046-58 pubmed publisher
    ..Heterozygous p53+/?31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms...
  50. Xiong S. Mouse models of Mdm2 and Mdm4 and their clinical implications. Chin J Cancer. 2013;32:371-5 pubmed publisher
    Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53. Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models...
  51. Wade M, Li Y, Wahl G. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13:83-96 pubmed publisher
    The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor...
  52. Shvarts A, Bazuine M, Dekker P, Ramos Y, Steegenga W, Merckx G, et al. Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. Genomics. 1997;43:34-42 pubmed
    We recently reported the identification of a mouse cDNA encoding a new p53-associating protein that we called Mdmx because of its structural similarity to Mdm2, a well-known p53-binding protein...
  53. Giglio S, Mancini F, Pellegrino M, Di Conza G, Puxeddu E, Sacchi A, et al. Regulation of MDM4 (MDMX) function by p76(MDM2): a new facet in the control of p53 activity. Oncogene. 2010;29:5935-45 pubmed publisher
    Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90(MDM2), for a short protein, p76(MDM2) that lacks the p53-binding domain...
  54. Cai X, Yuan Z. Stochastic modeling and simulation of the p53-MDM2/MDMX loop. J Comput Biol. 2009;16:917-33 pubmed publisher
    ..The p53 tumor repressor is regulated through a negative feedback loop involving its transcriptional target MDM2. MDMX is also an essential negative regulator of p53...
  55. Zhang Y, Zeng S, Hao Q, Lu H. Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner. Dev Biol. 2017;423:34-45 pubmed publisher
    ..The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early ..
  56. Parant J, Lozano G. Disrupting TP53 in mouse models of human cancers. Hum Mutat. 2003;21:321-6 pubmed
    ..Loss of either of the p53 inhibitors mdm2 or mdm4 gives rise to a p53-dependent embryonic lethal phenotype...
  57. Barboza J, Iwakuma T, Terzian T, El Naggar A, Lozano G. Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol Cancer Res. 2008;6:947-54 pubmed publisher
    ..Loss of p53 function also occurs by overexpression of negative regulators such as MDM2 and MDM4. Deletion of Mdm2 or Mdm4 in mice results in p53-dependent embryo lethality due to constitutive p53 activity...
  58. Mancini F, Pieroni L, Monteleone V, Lucà R, Fici L, Luca E, et al. MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response. Oncogene. 2016;35:228-40 pubmed publisher
    The p53 inhibitor, MDM4 (MDMX) is a cytoplasmic protein with p53-activating function under DNA damage conditions. Particularly, MDM4 promotes phosphorylation of p53 at Ser46, a modification that precedes different p53 activities...
  59. Fang M, Simeonova I, Bardot B, Lejour V, Jaber S, Bouarich Bourimi R, et al. Mdm4 loss in mice expressing a p53 hypomorph alters tumor spectrum without improving survival. Oncogene. 2014;33:1336-9 pubmed publisher
    ..Overexpression of Mdm4, a p53 negative regulator, occurs in a significant fraction of human cancers...
  60. Terzian T, Torchia E, Dai D, Robinson S, Murao K, Stiegmann R, et al. p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation. Pigment Cell Melanoma Res. 2010;23:781-94 pubmed publisher
    ..To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the ‘high-p53’Mdm4+/? mouse to the well-established TP-ras0/+ murine melanoma progression model...
  61. Pant V, Lozano G. Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity. Oncotarget. 2014;5:1149-56 pubmed
    ..Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice...
  62. 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
    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...
  63. Markey M. Regulation of MDM4. Front Biosci (Landmark Ed). 2011;16:1144-56 pubmed
    Mouse double minute 4 (MDM4), also known as MDMX or HDMX (human MDMX), is a critical negative regulator of the tumor suppressor p53. Under normal growth conditions, MDM4 contributes to the repression of p53 activity...
  64. Xiong S, Pant V, Zhang Y, Aryal N, You M, Kusewitt D, et al. The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis. J Pathol. 2017;241:501-510 pubmed publisher
    The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives the spontaneous development of mostly lymphomas and sarcomas...
  65. Di Conza G, Mancini F, Buttarelli M, Pontecorvi A, Trimarchi F, Moretti F. MDM4 enhances p53 stability by promoting an active conformation of the protein upon DNA damage. Cell Cycle. 2012;11:749-60 pubmed publisher
    ..p53 levels are regulated by ubiquitin-dependent and -independent degradation pathways. MDM4 (MDMX) is an important regulator of p53, able to both stimulate and antagonize p53 degradation...
  66. Zhang C, Zhang Q, Xie Y, He X, Xiang C, Hou X, et al. Mouse Double Minute 2 Actively Suppresses p53 Activity in Oocytes during Mouse Folliculogenesis. Am J Pathol. 2017;187:339-351 pubmed publisher
    ..Negative regulations of p53 by mouse double minute 2 (MDM2) and its homolog MDM4 are an integrated component of the network and have been implicated in regulating the stress responses and the ..
  67. Steinman H, Hoover K, Keeler M, Sands A, Jones S. Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene. 2005;24:7935-40 pubmed
    The Mdm2 and Mdm4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p53 tumor suppressor protein and inhibit p53 activity...
  68. Valentin Vega Y, Box N, Terzian T, Lozano G. Mdm4 loss in the intestinal epithelium leads to compartmentalized cell death but no tissue abnormalities. Differentiation. 2009;77:442-9 pubmed publisher
    b>Mdm4 is a critical inhibitor of the p53 tumor suppressor. Mdm4 null mice die early during embryogenesis due to increased p53 activity...
  69. Menendez S, Goh A, Camus S, Ng K, Kua N, Badal V, et al. MDM4 downregulates p53 transcriptional activity and response to stress during differentiation. Cell Cycle. 2011;10:1100-8 pubmed
    ..levels and activity are usually primarily controlled by the ubiquitin ligase MDM2, we identify the MDM2 homolog MDM4 as the key modulator of p53 activity in differentiating ES cells...
  70. Yokoyama M, Okada S, Nakagomi A, Moriya J, Shimizu I, Nojima A, et al. Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. Cell Rep. 2014;7:1691-1703 pubmed publisher
    ..These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity. ..