MDM4

Summary

Gene Symbol: MDM4
Description: MDM4, p53 regulator
Alias: HDMX, MDMX, MRP1, protein Mdm4, MDM4 protein variant G, MDM4 protein variant Y, MDM4-related protein 1, Mdm4 p53 binding protein homolog, double minute 4, human homolog of; p53-binding protein, mdm2-like p53-binding protein, protein Mdmx
Species: human
Products:     MDM4

Top Publications

  1. Riemenschneider M, Knobbe C, Reifenberger G. Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target. Int J Cancer. 2003;104:752-7 pubmed
    We previously reported on the amplification and overexpression of the mouse double minute 4 homolog gene (MDM4) from 1q32 in a subset of malignant gliomas (Riemenschneider et al., Cancer Res 1999;59:6091-6)...
  2. Elias B, Laine A, RONAI Z. Phosphorylation of MdmX by CDK2/Cdc2(p34) is required for nuclear export of Mdm2. Oncogene. 2005;24:2574-9 pubmed
    Mdm2 and MdmX function as cellular regulators of the p53 tumor suppressor protein...
  3. Prodosmo A, Giglio S, Moretti S, Mancini F, Barbi F, Avenia N, et al. Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. J Mol Med (Berl). 2008;86:585-96 pubmed publisher
    ..A new p53 regulator, MDM4 (a.k.a. MDMX or HDMX) an analog of MDM2, represents a new oncogene although its impact on tumor properties remains largely ..
  4. 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
    ..b>MDMX is structurally related to MDM2 and also binds to p53. However, the function of MDMX has not been clarified yet...
  5. Gilkes D, Pan Y, Coppola D, Yeatman T, Reuther G, Chen J. Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol. 2008;28:1999-2010 pubmed publisher
    b>MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development...
  6. Ghosh M, Weghorst K, Berberich S. MdmX inhibits ARF mediated Mdm2 sumoylation. Cell Cycle. 2005;4:604-8 pubmed
    ..In this present work, we report that MdmX can undergo ARF-mediated sumoylation similar to that reported for Mdm2...
  7. Zhu Y, Poyurovsky M, Li Y, Biderman L, Stahl J, Jacq X, et al. Ribosomal protein S7 is both a regulator and a substrate of MDM2. Mol Cell. 2009;35:316-26 pubmed publisher
    ..Notably, the MDM2 homolog MDMX facilitates the inhibition of MDM2 E3 ligase activity by S7...
  8. 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...
  9. Pan Y, Chen J. Modification of MDMX by sumoylation. Biochem Biophys Res Commun. 2005;332:702-9 pubmed
    b>MDMX is a homolog of MDM2 and is critical for regulating p53 function during mouse development...

More Information

Publications97

  1. Chen L, Li C, Pan Y, Chen J. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol. 2005;25:6509-20 pubmed
    b>MDMX is a homolog of MDM2 that is critical for regulating p53 function during mouse development. MDMX degradation is regulated by MDM2-mediated ubiquitination. Whether there are other mechanisms of MDMX regulation is largely unknown...
  2. Miller K, Kelley K, Tuttle R, Berberich S. HdmX overexpression inhibits oncogene induced cellular senescence. Cell Cycle. 2010;9:3376-82 pubmed publisher
    ..In the present study we show that HdmX, a negative regulator of p53, impacts the senescence pathway...
  3. 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...
  4. Popowicz G, Czarna A, Holak T. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle. 2008;7:2441-3 pubmed
    The Mdmx oncoprotein has only recently emerged as a critical-independent to Mdm2-regulator of p53 activation...
  5. 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
    ..Here we report that MDM2 physically interacts with a structurally related protein termed MDMX. The results obtained in these studies provide evidence that C-terminal RING finger domains, contained within both ..
  6. 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
    ..For efficient degradation of p53 nuclear export appears to be required. The Mdmx protein, structurally homologous to Mdm2, does not target p53 for degradation, but even stabilizes both p53 and ..
  7. Jackson M, Lindstrom M, Berberich S. MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. J Biol Chem. 2001;276:25336-41 pubmed
    ..The primary regulator of p53 protein stability is the Mdm2 protein. ARF and MdmX are two proteins that have recently been shown to inhibit Mdm2-mediated degradation of p53 via distinct ..
  8. 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
    ..Here we report that the MDM2 analog, MDMX, also displays a similar activity. MDMX directly bound to p21 and mediated its proteasomal degradation...
  9. Veerakumarasivam A, Scott H, Chin S, Warren A, Wallard M, Grimmer D, et al. High-resolution array-based comparative genomic hybridization of bladder cancers identifies mouse double minute 4 (MDM4) as an amplification target exclusive of MDM2 and TP53. Clin Cancer Res. 2008;14:2527-34 pubmed publisher
    ..1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade...
  10. Allende Vega N, Sparks A, Lane D, Saville M. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene. 2010;29:432-41 pubmed publisher
    ..Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2...
  11. McEvoy J, Ulyanov A, Brennan R, Wu G, Pounds S, Zhang J, et al. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma. PLoS ONE. 2012;7:e42739 pubmed publisher
    ..p53 gene is intact in human retinoblastoma but the pathway is believed to be suppressed by increased expression of MDM4 (MDMX) and MDM2...
  12. Jin G, Cook S, Cui B, Chen W, Keir S, Killela P, et al. HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea. Neuro Oncol. 2010;12:956-66 pubmed publisher
    ..Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus...
  13. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen A. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle. 2005;4:1166-70 pubmed
    The p53 tumor suppressor protein has a major role in protecting genome integrity. Under normal circumstances Mdmx and Mdm2 control the activity of p53...
  14. Kawai H, Wiederschain D, Kitao H, Stuart J, Tsai K, Yuan Z. DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem. 2003;278:45946-53 pubmed
    Although genetic studies have demonstrated that MDMX is essential to maintain p53 activity at low levels in non-stressed cells, it is unknown whether MDMX regulates p53 activation by DNA damage...
  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
    ..HAUSP also modulates p53 stability indirectly by deubiquitination and stabilization of Hdm2. The Hdmx protein affects p53 stability as well through its interaction with and regulation of Hdm2...
  16. 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...
  17. de Graaf P, Little N, Ramos Y, Meulmeester E, Letteboer S, Jochemsen A. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem. 2003;278:38315-24 pubmed
    ..Little is known about the regulation of Hdmx expression levels, apart from the observation that the Mdmx protein can be cleaved by caspase-3 in a p53-inducible manner...
  18. 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...
  19. Mancini F, Di Conza G, Moretti F. MDM4 (MDMX) and its Transcript Variants. Curr Genomics. 2009;10:42-50 pubmed publisher
    ..Alterations of their gene status, mainly amplification events, have been frequently observed in human tumors.MDM4 is one of the two members of the MDM family...
  20. Sabbatini P, McCormick F. MDMX inhibits the p300/CBP-mediated acetylation of p53. DNA Cell Biol. 2002;21:519-25 pubmed
    ..b>MDMX is an MDM2-like protein that shares with MDM2 the ability to interact with p53 and, in turn, inhibit p53-mediated ..
  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
    ..and selectivity of different members of the p53 family (p53, p63, and p73) and the MDM2 family (MDM2 and MDMX)...
  22. 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...
  23. Giglio S, Mancini F, Gentiletti F, Sparaco G, Felicioni L, Barassi F, et al. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer Res. 2005;65:9687-94 pubmed
    The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact...
  24. Liu L, Fan L, Fang C, Zou Z, Yang S, Zhang L, et al. S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia. Cancer Sci. 2012;103:2056-63 pubmed publisher
    The purpose of the present study was to investigate the prognostic significance of murine double minute 4 (MDM4) in chronic lymphocytic leukemia (CLL) and to characterize the role of MDM4 in the p53 pathway...
  25. Jin Y, Dai M, Lu S, Xu Y, Luo Z, Zhao Y, et al. 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J. 2006;25:1207-18 pubmed
    It has been shown that MDMX inhibits the activity of the tumor suppressor p53 by primarily cooperating with the p53 feedback regulator MDM2. Here, our study shows that this inhibition can be overcome by 14-3-3gamma and Chk1...
  26. 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...
  27. Garcia Closas M, Couch F, Lindstrom S, Michailidou K, Schmidt M, Brook M, et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013;45:392-8, 398e1-2 pubmed publisher
    ..SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4...
  28. 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
    ..Mdm2 can bind to itself and to the structurally related protein MdmX, and these interactions involve the RING finger domain of Mdm2 and MdmX, respectively...
  29. 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...
  30. Li B, Cheng Q, Li Z, Chen J. p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors. Cell Cycle. 2010;9:1411-20 pubmed
    ..Knockdown of MDMX cooperates with Nutlin to activate p53...
  31. Lenos K, Jochemsen A. Functions of MDMX in the modulation of the p53-response. J Biomed Biotechnol. 2011;2011:876173 pubmed publisher
    The MDM family proteins MDM2 and MDMX are two critical regulators of the p53 tumor suppressor protein. Expression of both proteins is necessary for allowing the embryonal development by keeping the activity of p53 in check...
  32. 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...
  33. Herman A, Hayano M, Poyurovsky M, Shimada K, Skouta R, Prives C, et al. Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov. 2011;1:312-25 pubmed publisher
    ..We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents.
  34. 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...
  35. Lopez Pajares V, Kim M, Yuan Z. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. J Biol Chem. 2008;283:13707-13 pubmed publisher
    ..We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation...
  36. 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...
  37. Laurie N, Donovan S, Shih C, Zhang J, Mills N, Fuller C, et al. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006;444:61-6 pubmed
    ..In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis...
  38. Tang Y, Zhao W, Chen Y, Zhao Y, Gu W. Acetylation is indispensable for p53 activation. Cell. 2008;133:612-26 pubmed publisher
    ..Our study identifies p53 acetylation as an indispensable event that destabilizes the p53-Mdm2 interaction and enables the p53-mediated stress response. ..
  39. 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 (∼65%) of stage ..
  40. Valentin Vega Y, Barboza J, Chau G, El Naggar A, Lozano G. High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas. Hum Pathol. 2007;38:1553-62 pubmed
    ..A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood...
  41. Liu J, Tang X, Li M, Lu C, Shi J, Zhou L, et al. Functional MDM4 rs4245739 genetic variant, alone and in combination with P53 Arg72Pro polymorphism, contributes to breast cancer susceptibility. Breast Cancer Res Treat. 2013;140:151-7 pubmed publisher
    The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function...
  42. 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...
  43. Linke K, Mace P, Smith C, Vaux D, Silke J, Day C. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ. 2008;15:841-8 pubmed publisher
    ..During normal non-stress conditions p53 is targeted for degradation by MDM2. MDM2 can also target itself and MDMX for degradation...
  44. 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...
  45. Bartel F, Schulz J, Böhnke A, Blümke K, Kappler M, Bache M, et al. Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis. Int J Cancer. 2005;117:469-75 pubmed
    The product of the HDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53...
  46. Biderman L, Poyurovsky M, Assia Y, Manley J, Prives C. MdmX is required for p53 interaction with and full induction of the Mdm2 promoter after cellular stress. Mol Cell Biol. 2012;32:1214-25 pubmed publisher
    ..The closely related Mdm2 homolog, MdmX, is also considered to be a general inhibitor of transactivation by p53, through binding to the p53 activation ..
  47. 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...
  48. 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...
  49. Heminger K, Markey M, Mpagi M, Berberich S. Alterations in gene expression and sensitivity to genotoxic stress following HdmX or Hdm2 knockdown in human tumor cells harboring wild-type p53. Aging (Albany NY). 2009;1:89-108 pubmed
    ..Our laboratory has been interested in tumor cells possessing wild-type p53 protein and elevated levels of HdmX and/or Hdm2, two critical negative regulators of p53 function...
  50. Joseph T, Madhumalar A, Brown C, Lane D, Verma C. Differential binding of p53 and nutlin to MDM2 and MDMX: computational studies. Cell Cycle. 2010;9:1167-81 pubmed
    ..One such defect is the overexpression of the MDM2 and MDMX proteins. This has led to an intense effort to develop inhibitors of p53-MDM2/MDMX interactions...
  51. 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...
  52. Strachan G, Jordan Sciutto K, Rallapalli R, Tuan R, Hall D. The E2F-1 transcription factor is negatively regulated by its interaction with the MDMX protein. J Cell Biochem. 2003;88:557-68 pubmed
    ..Here we identify the MDMX oncoprotein as an E2F-1-binding factor, from a yeast-two hybrid screen using a portion of the E2F-1 protein as &..
  53. 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...
  54. Wunderlich M, Ghosh M, Weghorst K, Berberich S. MdmX represses E2F1 transactivation. Cell Cycle. 2004;3:472-8 pubmed
    Based on knockout mouse studies, Mdm2 and MdmX have been identified as critical regulators of the p53 tumor suppressor protein, at least during early development...
  55. Stad R, Ramos Y, Little N, Grivell S, Attema J, van der Eb A, et al. Hdmx stabilizes Mdm2 and p53. J Biol Chem. 2000;275:28039-44 pubmed
    ..In this study we investigated the effect of the human Mdm2 homologue Hdmx on p53 stability...
  56. Gentiletti F, Mancini F, D Angelo M, Sacchi A, Pontecorvi A, Jochemsen A, et al. MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts. Oncogene. 2002;21:867-77 pubmed
    b>MDMX is a p53 binding protein, which shares a high degree of homology with MDM2, a negative regulator of the tumor suppressor p53. MDMX has been shown to counteract MDM2-dependent p53 degradation and to stabilize p53 in its inactive form...
  57. Mancini F, Gentiletti F, D Angelo M, Giglio S, Nanni S, D Angelo C, et al. MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis. J Biol Chem. 2004;279:8169-80 pubmed
    Rescue of embryonic lethality in MDM4(-/-) mice through concomitant loss of p53 has revealed a functional partnership between the two proteins...
  58. Lenos K, de Lange J, Teunisse A, Lodder K, Verlaan de Vries M, Wiercinska E, et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol Cancer. 2011;10:111 pubmed publisher
    ..The two main inhibitors of p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed in wild-type p53 tumors...
  59. 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
    ..RMS tumors has identified specific alternative splice variants of the oncogenes Murine Double Minute 2 (MDM2) and MDM4 as potential biomarkers for RMS...
  60. 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. Recent reports have provided insight into the complex mechanisms that regulate these two proteins and have ..
  61. Pereg Y, Lam S, Teunisse A, Biton S, Meulmeester E, Mittelman L, et al. Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage. Mol Cell Biol. 2006;26:6819-31 pubmed
    ..posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB ..
  62. Kulkarni D, Vazquez A, Haffty B, Bandera E, Hu W, Sun Y, et al. A polymorphic variant in human MDM4 associates with accelerated age of onset of estrogen receptor negative breast cancer. Carcinogenesis. 2009;30:1910-5 pubmed publisher
    Murine double minute 4 (MDM4) shares significant structural homology with murine double minute 2 (MDM2) and interacts and regulates transcriptional activity of the tumor suppressor p53...
  63. 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...
  64. Zuckerman V, Lenos K, Popowicz G, Silberman I, Grossman T, Marine J, et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J Biol Chem. 2009;284:4031-9 pubmed publisher
    ..For this to occur, p53 must be relieved from its major inhibitors, Mdm2 (Hdm2 in humans) and Mdmx (Mdm4; Hdmx in humans)...
  65. 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...
  66. Hu B, Gilkes D, Chen J. Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. Cancer Res. 2007;67:8810-7 pubmed
    The p53 tumor suppressor plays a key role in protection against malignant transformation. MDM2 and MDMX are important regulators of the transcriptional activity and stability of p53 by binding to its NH(2) terminus...
  67. Ongkeko W, Wang X, Siu W, Lau A, Yamashita K, Harris A, et al. MDM2 and MDMX bind and stabilize the p53-related protein p73. Curr Biol. 1999;9:829-32 pubmed
    ..Like MDM2, the MDM2-related protein MDMX also bound p73 and stabilized the level of p73...
  68. 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...
  69. Pereg Y, Shkedy D, de Graaf P, Meulmeester E, Edelson Averbukh M, Salek M, et al. Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc Natl Acad Sci U S A. 2005;102:5056-61 pubmed
    ..Here we show that efficient damage-induced degradation of human Hdmx depends on functional ATM and at least three sites on the Hdmx that are phosphorylated in response to DSBs...
  70. 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)...
  71. 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
    mdm2 and mdmx oncogenes play essential yet non-redundant roles in synergistic inactivation of the tumor suppressor, p53...
  72. Kallen J, Goepfert A, Blechschmidt A, Izaac A, Geiser M, Tavares G, et al. Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes. J Biol Chem. 2009;284:8812-21 pubmed publisher
    p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu(26), Trp(23), and Phe(19) are crucial to mediate these interactions...
  73. Sarkari F, La Delfa A, Arrowsmith C, Frappier L, Sheng Y, Saridakis V. Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7. J Mol Biol. 2010;402:825-37 pubmed publisher
    ..The ability of USP7 to also deubiquitinate and control the turnover of HdmX was recently demonstrated...
  74. Zhou L, Zhang X, Li Z, Zhou C, Li M, Tang X, et al. Association of a genetic variation in a miR-191 binding site in MDM4 with risk of esophageal squamous cell carcinoma. PLoS ONE. 2013;8:e64331 pubmed publisher
    As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function...
  75. Gilkes D, Chen L, Chen J. MDMX regulation of p53 response to ribosomal stress. EMBO J. 2006;25:5614-25 pubmed
    ..We found that p53 activation by ribosomal stress requires degradation of MDMX in an MDM2-dependent fashion...
  76. Pei D, Zhang Y, Zheng J. Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget. 2012;3:228-35 pubmed
    ..Mdm2 and Mdmx are recognized as the main p53 negative regulators...
  77. Kadakia M, Brown T, McGorry M, Berberich S. MdmX inhibits Smad transactivation. Oncogene. 2002;21:8776-85 pubmed
    ..Our goal in this study was to examine whether overexpression of Mdm2 or MdmX, a Mdm2-related protein, could affect Smad-induced transactivation...
  78. Uldrijan S, Pannekoek W, Vousden K. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J. 2007;26:102-12 pubmed
    ..of the C-terminal tail correlated with a failure of these mutants to oligomerize with MDM2, or with the related protein MDMX (HDMX)...
  79. Pazgier M, Liu M, Zou G, Yuan W, Li C, Li C, et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A. 2009;106:4665-70 pubmed publisher
    The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53--a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53...
  80. Macchiarulo A, Giacchè N, Carotti A, Baroni M, Cruciani G, Pellicciari R. Targeting the conformational transitions of MDM2 and MDMX: insights into dissimilarities and similarities of p53 recognition. J Chem Inf Model. 2008;48:1999-2009 pubmed publisher
    MDM2 and MDMX are oncogenic homologue proteins that regulate the activity and stability of p53, a tumor suppressor protein involved in more than 50% of human cancers...
  81. Atwal G, Kirchhoff T, Bond E, Montagna M, Monagna M, Menin C, et al. Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene. Proc Natl Acad Sci U S A. 2009;106:10236-41 pubmed publisher
    ..In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations...
  82. 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...
  83. Pan Y, Chen J. MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol. 2003;23:5113-21 pubmed
    ..Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53...
  84. LeBron C, Chen L, Gilkes D, Chen J. Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. EMBO J. 2006;25:1196-206 pubmed
    The MDM2 homolog MDMX is an important regulator of p53 during mouse embryonic development. DNA damage promotes MDMX phosphorylation, nuclear translocation, and degradation by MDM2...
  85. 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
    ..A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target ..
  86. 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 ..
  87. Uchida C, Miwa S, Isobe T, Kitagawa K, Hattori T, Oda T, et al. Effects of MdmX on Mdm2-mediated downregulation of pRB. FEBS Lett. 2006;580:1753-8 pubmed
    ..In the present study, we assessed the effects of MdmX, a structural homolog of Mdm2, on the Mdm2-mediated ubiquitination of pRB...
  88. Wynendaele J, Böhnke A, Leucci E, Nielsen S, Lambertz I, Hammer S, et al. An illegitimate microRNA target site within the 3' UTR of MDM4 affects ovarian cancer progression and chemosensitivity. Cancer Res. 2010;70:9641-9 pubmed publisher
    Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function...