Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MDM4 (Murine Double Minute 4)

  • Annie Huang
  • Emily Yang
  • Manabu Kurokawa
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101575

Synonyms

Historical Background

Mouse Mdm4 (murine double minute 4) was first identified in an attempt to isolate a novel human p53-binding protein by screening a mouse cDNA library (Shvarts et al. 1996). Subsequently, its human homolog, MDM4, was cloned through a screen that used mouse Mdm4 cDNA as probe (Shvarts et al. 1997). Human MDM4 protein is 90% similar to mouse Mdm4 (Shvarts et al. 1997), with the greatest homology in the N-terminal p53-binding domain, and is ubiquitously expressed in tissues and organs (Shvarts et al. 1996; Shvarts et al. 1997). Importantly, MDM4 is homologous to MDM2, a key E3 ubiquitin ligase that negatively regulates the tumor suppressor p53 (Shvarts et al. 1996) (see also the MDM2 section). Therefore, overexpression of MDM4 leads to the suppression of p53 activity (Shvarts et al. 1996). However, subsequent...

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Notes

Acknowledgments

The work in the Kurokawa laboratory is supported by an NCI Career Development Award R00 CA140948 (to M.K.), an American Cancer Society Institutional Research Grant IRG-82-003-30 (to M.K.), a Norris Cotton Cancer Center Prouty grant (to M.K.), and a Norris Cotton Cancer Center Holland Award (to M.K.).

References

  1. Allende-Vega N, Sparks A, Lane DP, Saville MK. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene. 2010;29:432–41.  https://doi.org/10.1038/onc.2009.330.CrossRefPubMedGoogle Scholar
  2. Bardot B, Bouarich-Bourimi R, Leemput J, Lejour V, Hamon A, Plancke L, Jochemsen AG, Simeonova I, Fang M, Toledo F. Mice engineered for an obligatory Mdm4 exon skipping express higher levels of the Mdm4-S isoform but exhibit increased p53 activity. Oncogene. 2015;34:2943–8.  https://doi.org/10.1038/onc.2014.230.CrossRefPubMedGoogle Scholar
  3. Bartel F, Schulz J, Böhnke A, Blümke K, Kappler M, Bache M, Schmidt H, Würl P, Taubert H, Hauptmann S. 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.  https://doi.org/10.1002/ijc.21206.CrossRefPubMedGoogle Scholar
  4. Carrillo AM, Bouska A, Arrate MP, Eischen CM. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene. 2015;34:846–56.  https://doi.org/10.1038/onc.2014.27.CrossRefPubMedGoogle Scholar
  5. Chandler DS, Singh RK, Caldwell LC, Bitler JL, Lozano G. Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. Cancer Res. 2006;66:9502–8.  https://doi.org/10.1158/0008-5472.CAN-05-4271.CrossRefPubMedGoogle Scholar
  6. Chen L, Gilkes DM, Pan Y, Lane WS, Chen J. ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J. 2005a;24:3411–22.  https://doi.org/10.1038/sj.emboj.7600812.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen L, Li C, Pan Y, Chen J. Regulation of p53-MDMX interaction by casein kinase 1 α. Mol Cell Biol. 2005b;25:6509–20.  https://doi.org/10.1128/MCB.25.15.6509-6520.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  8. de Graaf P, Little NA, Ramos YF, Meulmeester E, Letteboer SJ, Jochemsen AG. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem. 2003;278:38315–24.  https://doi.org/10.1074/jbc.M213034200.CrossRefPubMedGoogle Scholar
  9. Dewaele M, Tabaglio T, Willekens K, Bezzi M, Teo SX, et al. Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. J Clin Invest. 2016;126:68–84.  https://doi.org/10.1172/JCI82534.CrossRefPubMedGoogle Scholar
  10. 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.  https://doi.org/10.1038/sj.onc.1208488.PubMedCrossRefGoogle Scholar
  11. Finch RA, Donoviel DB, Potter D, Shi M, Fan A, Freed DD, Wang CY, Zambrowicz BP, Ramirez-Solis R, Sands AT, Zhang N. mdmx is a negative regulator of p53 activity in vivo. Cancer Res. 2002;62:3221–5.PubMedGoogle Scholar
  12. Francoz S, Froment P, Bogaerts S, De Clercq S, Maetens M, Doumont G, Bellefroid E, Marine JC. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci USA. 2006;103:3232–7.  https://doi.org/10.1073/pnas.0508476103.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18:1239–47.  https://doi.org/10.1038/nm.2863.CrossRefPubMedGoogle Scholar
  14. Giglio S, Mancini F, Gentiletti F, Sparaco G, Felicioni L, Barassi F, Martella C, Prodosmo A, Iacovelli S, Buttitta F, Farsetti A, Soddu S, Marchetti A, Sacchi A, Pontecorvi A, Moretti F. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer Res. 2005;65:9687–94.  https://doi.org/10.1158/0008-5472.CAN-05-0450.CrossRefPubMedGoogle Scholar
  15. Graves B, Thompson T, Xia M, Janson C, Lukacs C, Deo D, Di Lello P, Fry D, Garvie C, Huang KS, Gao L, Tovar C, Lovey A, Wanner J, Vassilev LT. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci USA. 2012;109:11788–93.  https://doi.org/10.1073/pnas.1203789109.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Grier JD, Xiong S, Elizondo-Fraire AC, Parant JM, Lozano G. Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol Cell Biol. 2006;26:192–8.  https://doi.org/10.1128/MCB.26.1.192-198.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem. 2006;281:33030–5.  https://doi.org/10.1074/jbc.C600147200.CrossRefPubMedGoogle Scholar
  18. Kawai H, Wiederschain D, Kitao H, Stuart J, Tsai KK, Yuan ZM. DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem. 2003;278:45946–53.  https://doi.org/10.1074/jbc.M308295200.CrossRefPubMedGoogle Scholar
  19. Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, et al. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006;444:61–6.  https://doi.org/10.1038/nature05194.CrossRefPubMedGoogle Scholar
  20. Linares LK, Hengstermann A, Ciechanover A, Müller S, Scheffner M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci USA. 2003;100:12009–14.  https://doi.org/10.1073/pnas.2030930100.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lopez-Pajares V, Kim MM, Yuan ZM. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. J Biol Chem. 2008;283:13707–13.  https://doi.org/10.1074/jbc.M710030200.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Matijasevic Z, Steinman HA, Hoover K, Jones SN. MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice. Mol Cell Biol. 2008;28:1265–73.  https://doi.org/10.1128/MCB.01108-07.CrossRefPubMedGoogle Scholar
  23. Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell. 2005;18:565–76.  https://doi.org/10.1016/j.molcel.2005.04.024.CrossRefPubMedCentralPubMedGoogle Scholar
  24. Migliorini D, Danovi D, Colombo E, Carbone R, Pelicci PG, Marine JC. Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. J Biol Chem. 2002a;277:7318–23.  https://doi.org/10.1074/jbc.M108795200.CrossRefPubMedGoogle Scholar
  25. Migliorini D, Lazzerini Denchi E, Danovi D, Jochemsen A, Capillo M, Gobbi A, Helin K, Pelicci PG, Marine JC. Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol. 2002b;22:5527–38.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Pan Y, Chen J. MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol. 2003;23:5113–21.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Pan Y, Chen J. Modification of MDMX by sumoylation. Biochem Biophys Res Commun. 2005;332:702–9.  https://doi.org/10.1016/j.bbrc.2005.05.012.CrossRefPubMedGoogle Scholar
  28. Pant V, Xiong S, Iwakuma T, Quintás-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 USA. 2011;108:11995–2000.  https://doi.org/10.1073/pnas.1102241108.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG, Lozano G. 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.  https://doi.org/10.1038/ng714.CrossRefPubMedGoogle Scholar
  30. Pereg Y, Lam S, Teunisse A, Biton S, Meulmeester E, Mittelman L, Buscemi G, Okamoto K, Taya Y, Shiloh Y, Jochemsen AG. Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage. Mol Cell Biol. 2006;26:6819–31.  https://doi.org/10.1128/MCB.00562-06.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Rallapalli R, Strachan G, Cho B, Mercer E, Hall DJ. 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.  https://doi.org/10.1074/jbc.274.12.8299.CrossRefPubMedGoogle Scholar
  32. Rallapalli R, Strachan G, Tuan RS, Hall DJ. Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells. J Cell Biochem. 2003;89:563–675.  https://doi.org/10.1002/jcb.10535.CrossRefPubMedGoogle Scholar
  33. Riemenschneider MJ, Büschges R, Wolter M, Reifenberger J, Boström J, Kraus JA, Schlegel U, Reifenberger G. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 1999;59(24):6091–6.PubMedGoogle Scholar
  34. Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996;15:5349–57.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Shvarts A, Bazuine M, Dekker P, Ramos Y, Steegenga WT. Isolation and Identification of the Human Homolog of a New p53-Binding Protein. Mdmx Genomics. 1997;43:34–42.  https://doi.org/10.1006/geno.1997.4775.CrossRefPubMedGoogle Scholar
  36. Stad R, Ramos YF, Little N, Grivell S, Attema J, van Der Eb AJ, Jochemsen AG. Hdmx stabilizes Mdm2 and p53. J Biol Chem. 2000;275:28039–44.  https://doi.org/10.1074/jbc.M003496200.CrossRefPubMedGoogle Scholar
  37. Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP, Saville MK, Jochemsen AG. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep. 2001;2:1029–34.  https://doi.org/10.1093/embo-reports/kve227.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Steinman HA, Hoover KM, Keeler ML, Sands AT, Jones SN. Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene. 2005;24:7935–40.  https://doi.org/10.1038/sj.onc.1208930.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. Wade M, Wahl GM. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res. 2009;7:1–11.  https://doi.org/10.1158/1541-7786.MCR-08-0423.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Wang X, Arooz T, Siu WY, Chiu CH, Lau A, Yamashita K, Poon RY. MDM2 and MDMX can interact differently with ARF and members of the p53 family. FEBS Lett. 2001;490:202–8.CrossRefPubMedGoogle Scholar
  42. Xiong S, Pant V, Suh YA, Van Pelt CS, Wang Y, Valentin-Vega YA, Post SM, Lozano G. Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res. 2010;70:7148–54.  https://doi.org/10.1158/0008-5472.CAN-10-1457.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zuckerman V, Lenos K, Popowicz GM, Silberman I, Grossman T, et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J Biol Chem. 2009;284:4031–9.  https://doi.org/10.1074/jbc.M809211200.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular and Systems BiologyGeisel School of Medicine at DartmouthHanoverUSA
  2. 2.Norris Cotton Cancer CenterLebanonUSA