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

Top Publications

  1. pmc Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery
    Marco Bezzi
    Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics, and Differentiation, Institute of Molecular and Cell Biology IMCB, A STAR Agency for Science, Technology, and Research, Singapore 138673, Singapore
    Genes Dev 27:1903-16. 2013
  2. pmc Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
    Jason D Grier
    The University of Texas Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cell Biol 26:192-8. 2006
  3. pmc Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
    Shunbin Xiong
    Department of Molecular Genetics, University of Texas MD Anderson Cancer Center, Houston, 77030, USA
    Proc Natl Acad Sci U S A 103:3226-31. 2006
  4. pmc 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
    Anna Phillips
    Southampton Cancer Research UK Centre, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, United Kingdom
    J Biol Chem 285:29111-27. 2010
  5. ncbi Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
    J C Marine
    Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology VIB, University of Ghent, Technologiepark, 927, Ghent B 9052, Belgium
    Cell Death Differ 13:927-34. 2006
  6. ncbi Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death
    L S M Boesten
    Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
    Cell Death Differ 13:2089-98. 2006
  7. ncbi Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4
    Dawn S Chandler
    Center for Childhood Cancer, Columbus Children s Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
    Cancer Res 66:9502-8. 2006
  8. pmc MDMX: a novel p53-binding protein with some functional properties of MDM2
    A Shvarts
    Laboratory of Molecular Carcinogenesis, Sylvius Laboratories, Leiden University, The Netherlands
    EMBO J 15:5349-57. 1996
  9. ncbi Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
    Franck Toledo
    Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 Rue d Ulm, 75248 Paris Cedex 05, France
    Nat Rev Cancer 6:909-23. 2006
  10. pmc Validation of MdmX as a therapeutic target for reactivating p53 in tumors
    Daniel Garcia
    Department of Pathology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143, USA
    Genes Dev 25:1746-57. 2011

Scientific Experts

  • Franck Toledo
  • Michael P Markey
  • Shunbin Xiong
  • Xinjiang Wang
  • Jean Christophe W Marine
  • Dawn S Chandler
  • Xiaodong Cai
  • Lei Huang
  • Guillermina Lozano
  • Vinod Pant
  • Tamara Terzian
  • Aart G Jochemsen
  • Jun Ho Lee
  • Heather A Steinman
  • Sarah De Clercq
  • Stephen N Jones
  • Marion Maetens
  • John M Parant
  • Tomoo Iwakuma
  • Sarah Francoz
  • Giusy Di Conza
  • Kristiaan Lenos
  • Francesca Mancini
  • F Mancini
  • Yunyuan V Wang
  • A G Jochemsen
  • Michael I Carr
  • Gabriel Livera
  • Mehrnoosh Tashakori
  • A M Carrillo
  • Xue Yan He
  • Inês Crespo
  • Shinseog Kim
  • Masataka Yokoyama
  • Chun lin Wang
  • Laura A Tollini
  • Lai Chen
  • Geng Liu
  • Hidehiko Kawai
  • Marco Bezzi
  • Iva Simeonova
  • Yanping Zhang
  • Erik Meulmeester
  • Qin Zhang
  • Hilary V Clegg
  • Heng Yang
  • Alfonso Quintas-Cardama
  • Linda Vuong
  • Hua Lu
  • Sergio Menendez
  • Daniel Garcia
  • Arthur T Sands
  • Fabiola Moretti
  • Alfredo Pontecorvi
  • Geoffrey M Wahl
  • S Giglio
  • Davide Danovi
  • A Pontecorvi
  • F Moretti
  • Elizabeth A Slee
  • G Di Conza
  • Saravanakumar Iyappan
  • Anna Phillips
  • Domenico Migliorini
  • Yasmine A Valentin-Vega
  • Neil F Box
  • Juan A Barboza
  • Zdenka Matijasevic
  • Mi Sung Kim
  • S Benosman
  • Gilles Doumont
  • Pascal Froment
  • Eric Bellefroid
  • Jason D Grier
  • L S M Boesten
  • Dmitri Wiederschain
  • Zhi Min Yuan
  • Anne Simone Parent
  • A Shvarts
  • Justine E Roderick
  • Rustem Uzbekov
  • Sophie Fouchécourt
  • M James You
  • Hugh S Gannon
  • Alberto Gobbi
  • Arturo Chavez-Reyes
  • Kristian Helin
  • Pier Giuseppe Pelicci
  • Yun Zhang
  • Michelle A Kelliher

Detail Information

Publications74

  1. pmc Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery
    Marco Bezzi
    Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics, and Differentiation, Institute of Molecular and Cell Biology IMCB, A STAR Agency for Science, Technology, and Research, Singapore 138673, Singapore
    Genes Dev 27:1903-16. 2013
    ..We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to ..
  2. pmc Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
    Jason D Grier
    The University of Texas Graduate School of Biomedical Sciences, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cell Biol 26:192-8. 2006
    ..Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors...
  3. pmc Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
    Shunbin Xiong
    Department of Molecular Genetics, University of Texas MD Anderson Cancer Center, Houston, 77030, USA
    Proc Natl Acad Sci U S A 103:3226-31. 2006
    Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent...
  4. pmc 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
    Anna Phillips
    Southampton Cancer Research UK Centre, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, United Kingdom
    J Biol Chem 285:29111-27. 2010
    ....
  5. ncbi Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
    J C Marine
    Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology VIB, University of Ghent, Technologiepark, 927, Ghent B 9052, Belgium
    Cell Death Differ 13:927-34. 2006
  6. ncbi Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death
    L S M Boesten
    Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
    Cell Death Differ 13:2089-98. 2006
    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...
  7. ncbi Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4
    Dawn S Chandler
    Center for Childhood Cancer, Columbus Children s Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
    Cancer Res 66:9502-8. 2006
    ..The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53...
  8. pmc MDMX: a novel p53-binding protein with some functional properties of MDM2
    A Shvarts
    Laboratory of Molecular Carcinogenesis, Sylvius Laboratories, Leiden University, The Netherlands
    EMBO J 15:5349-57. 1996
    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...
  9. ncbi Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
    Franck Toledo
    Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 Rue d Ulm, 75248 Paris Cedex 05, France
    Nat Rev Cancer 6:909-23. 2006
    ..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. pmc Validation of MdmX as a therapeutic target for reactivating p53 in tumors
    Daniel Garcia
    Department of Pathology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143, USA
    Genes Dev 25:1746-57. 2011
    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...
  11. pmc Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development
    Tamara Terzian
    Department of Cancer Genetics, Box 1010, The University of Texas M D Anderson Cancer Center, Baylor College of Medicine, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Mol Cell Biol 27:5479-85. 2007
    ..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 ..
  12. ncbi Loss of Mdm4 results in p53-dependent dilated cardiomyopathy
    Shunbin Xiong
    Department of Cancer Genetics, The University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    Circulation 115:2925-30. 2007
    ..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...
  13. ncbi RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity
    Hidehiko Kawai
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Cancer Res 67:6026-30. 2007
    ..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 ..
  14. pmc The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity
    Vinod Pant
    Department of Genetics
    Genes Dev 27:1857-67. 2013
    ..Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies...
  15. pmc MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice
    Zdenka Matijasevic
    Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
    Mol Cell Biol 28:1265-73. 2008
    Mdm2 and MdmX are structurally related p53-binding proteins that function as critical negative regulators of p53 activity in embryonic and adult tissue...
  16. pmc Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases
    Yunyuan V Wang
    Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Cancer Cell 16:33-43. 2009
    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...
  17. pmc MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway
    Francesca Mancini
    Institute of Neurobiology and Molecular Medicine, National Council of Research, Rome, Italy
    EMBO J 28:1926-39. 2009
    b>MDM4 is a key regulator of p53, whose biological activities depend on both transcriptional activity and transcription-independent mitochondrial functions...
  18. ncbi Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2
    Erik Meulmeester
    Department of Molecular and Cell Biology, Leiden University Medical Center, P O Box 9503, 2300 RA Leiden, The Netherlands
    Mol Cell 18:565-76. 2005
    ..Importantly, impaired deubiquitination of Hdmx/Hdm2 by HAUSP contributes to the DNA damage-induced degradation of Hdmx and transient instability of Hdm2...
  19. pmc The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo
    Lei Huang
    Department of Medical Genetics, E Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Proc Natl Acad Sci U S A 108:12001-6. 2011
    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...
  20. ncbi A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity
    R Rallapalli
    Department of Biochemistry and Molecular Pharmacology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 274:8299-308. 1999
    The MDMX gene product is related to the MDM2 oncoprotein, both of which interact with the p53 tumor suppressor...
  21. pmc Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability
    Vinod Pant
    Department of Genetics, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 108:11995-2000. 2011
    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...
  22. ncbi Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53
    J Parant
    The University of Texas M D Anderson Cancer Center, Department of Molecular Genetics, Section of Cancer Genetics, Box 11, 1515 Holcombe Blvd, Houston, Texas, USA
    Nat Genet 29:92-5. 2001
    ..The recently discovered MDM2-related protein MDM4 (also known as MDMX) has some of the same properties as MDM2...
  23. ncbi Mutual dependence of MDM2 and MDMX in their functional inactivation of p53
    Jijie Gu
    Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    J Biol Chem 277:19251-4. 2002
    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...
  24. pmc Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models
    Tamara Terzian
    Department of Dermatology, UC Denver, Aurora, CO, USA
    J Pathol 224:540-52. 2011
    ..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...
  25. ncbi mdmx is a negative regulator of p53 activity in vivo
    Rick A Finch
    Lexicon Genetics, Inc, 4000 Research Forest Drive, The Woodlands, TX 77381, USA
    Cancer Res 62:3221-5. 2002
    ..Here we report that loss of mdmx, a p53-binding protein, results in midgestational embryo lethality, a phenotype that is completely rescued by the ..
  26. pmc Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development
    Domenico Migliorini
    Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy
    Mol Cell Biol 22:5527-38. 2002
    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...
  27. pmc MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination
    Xinjiang Wang
    Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
    J Biol Chem 286:23725-34. 2011
    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...
  28. ncbi Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth
    Heather A Steinman
    Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Oncogene 23:303-6. 2004
    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...
  29. pmc Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity
    Davide Danovi
    Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
    Mol Cell Biol 24:5835-43. 2004
    ..A role for Mdmx (or Mdm4) as a key negative regulator of p53 function in vivo has been established...
  30. pmc Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo
    Sarah De Clercq
    Laboratory For Molecular Cancer Biology, Department of Biomedical Molecular Biology, VIB UGent, Technologiepark, B 9052 Ghent, Belgium
    Mol Cell Biol 30:5394-405. 2010
    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...
  31. pmc Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4
    Shunbin Xiong
    Departments of Genetics and Veterinary Medicine and Surgery, The University of Texas M D Anderson Cancer Center Houston, TX 77030, USA
    Cancer Res 70:7148-54. 2010
    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...
  32. pmc Functions of MDMX in the modulation of the p53-response
    Kristiaan Lenos
    Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
    J Biomed Biotechnol 2011:876173. 2011
    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...
  33. doi Puzzling over MDM4-p53 network
    F Mancini
    Institute of Neurobiology and Molecular Medicine Fondazione Santa Lucia, CNR, Via del Fosso di Fiorano 64, 00143 Roma, Italy
    Int J Biochem Cell Biol 42:1080-3. 2010
    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...
  34. pmc Pattern of expression of p53, its family members, and regulators during early ocular development and in the post-mitotic retina
    Linda Vuong
    Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Invest Ophthalmol Vis Sci 53:4821-31. 2012
    ..To shed light on the role of p53 in retinal development and maintenance, this study investigated the pattern of expression of p53, its family members, and its regulators during the development of the mouse eye...
  35. pmc Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis
    Michael I Carr
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Cell Rep 16:2618-29. 2016
    ....
  36. doi Mutant mice lacking the p53 C-terminal domain model telomere syndromes
    Iva Simeonova
    Genetics of Tumor Suppression, Institut Curie, Centre de Recherche, 26 Rue d Ulm, 75248 Paris Cedex 05, France
    Cell Rep 3:2046-58. 2013
    ..Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms...
  37. doi Ubiquitin-specific protease 2a stabilizes MDM4 and facilitates the p53-mediated intrinsic apoptotic pathway in glioblastoma
    Chun lin Wang
    Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China, Department of Neurosurgery, the 105th Hospital of PLA, Hefei 230000, Anhui Province, China
    Carcinogenesis 35:1500-9. 2014
    The mouse double minute 4 (MDM4) oncoprotein may inhibit tumorigenesis by regulating the apoptotic mediator p53...
  38. pmc Mdmx promotes genomic instability independent of p53 and Mdm2
    A M Carrillo
    Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
    Oncogene 34:846-56. 2015
    The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor...
  39. pmc Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity
    Vinod Pant
    Department of Genetics, M D Anderson Cancer Center, Houston, Texas
    Oncotarget 5:1149-56. 2014
    ..Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice...
  40. pmc Mouse models of Mdm2 and Mdm4 and their clinical implications
    Shunbin Xiong
    Department of Genetics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Chin J Cancer 32:371-5. 2013
    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...
  41. doi Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity
    Masataka Yokoyama
    Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba 260 8670, Japan
    Cell Rep 7:1691-703. 2014
    ..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. ..
  42. pmc Regulation of p53 by Mdm2 E3 ligase function is dispensable in embryogenesis and development, but essential in response to DNA damage
    Laura A Tollini
    Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7512, USA Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7512, USA Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7512, USA
    Cancer Cell 26:235-47. 2014
    ..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...
  43. pmc PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos
    Shinseog Kim
    Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK Department of Physiology, Development, and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
    Mol Cell 56:564-79. 2014
    ..Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation...
  44. doi Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53-dependent and results in female sterility
    Gabriel Livera
    Laboratoire de Développement des Gonades, INSERM U967, CEA DSV iRCM SCSR LDG, Univ Paris Diderot, Sorbonne Paris Cité, Fontenay aux Roses, France
    FEBS Lett 590:2566-74. 2016
    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...
  45. doi p53 in the Myeloid Lineage Modulates an Inflammatory Microenvironment Limiting Initiation and Invasion of Intestinal Tumors
    Xue Yan He
    State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, 12 Xuefu Road, Pukou High Tec District, Nanjing, Jiangsu Province 210061, China
    Cell Rep 13:888-97. 2015
    ..Therefore, as a regulator of macrophage function, p53 is critical to protection against tumorigenesis in a non-cell-autonomous manner...
  46. pmc p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis
    Mehrnoosh Tashakori
    Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas The University of Texas Graduate School of Biomedical Sciences, Program in Genes and Development
    Mol Cancer Res 14:56-65. 2016
    b>Mdm4 negatively regulates the p53 tumor suppressor. Mdm4 loss in mice leads to an embryonic lethal phenotype that is p53-dependent...
  47. doi Molecular and Genomic Alterations in Glioblastoma Multiforme
    Inês Crespo
    Centre for Neurosciences and Cell Biology, Faculties of Pharmacy and Medicine, University of Coimbra, Coimbra, Portugal
    Am J Pathol 185:1820-33. 2015
    ..homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (..
  48. ncbi Disrupting TP53 in mouse models of human cancers
    John M Parant
    Department of Molecular Genetics, Section of Cancer Genetics, University of Texas M D Anderson Cancer Center, Houston, Texas 77030 4095, USA
    Hum Mutat 21:321-6. 2003
    ..Loss of either of the p53 inhibitors mdm2 or mdm4 gives rise to a p53-dependent embryonic lethal phenotype...
  49. pmc Downregulation of Mdm2 and Mdm4 enhances viral gene expression during adenovirus infection
    Heng Yang
    Department of Anatomy and Cell Biology, University of Florida Shands Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
    Cell Cycle 11:582-93. 2012
    ..Here, we show that shRNA-mediated knockdown of murine double minute (Mdm2) and its paralog Mdm4 enhanced the expression of early and late viral gene products during adenovirus (HAdV) infection...
  50. doi MDM4 enhances p53 stability by promoting an active conformation of the protein upon DNA damage
    Giusy Di Conza
    National Research Council of Italy, Cell Biology and Neurobiology Institute, Rome, Italy
    Cell Cycle 11:749-60. 2012
    ..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...
  51. pmc Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and consequent 14-3-3γ inactivation of MDMX protein
    Jun Ho Lee
    Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:20898-903. 2012
    ..Here, we showed that hypoxia could induce phosphorylation of MDMX at Ser-367 and enhance the binding of this phosphorylated MDMX to 14-3-3γ, consequently leading to p53 activation...
  52. pmc Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction
    Hilary V Clegg
    Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
    PLoS ONE 7:e38212. 2012
    ..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 ..
  53. doi Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development
    Qin Zhang
    The MOE Key Laboratory of Model Animal for Disease Study and the Model Animal Research Center, Nanjing University, Nanjing, China
    J Pathol 228:416-28. 2012
    ..p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post-translational level...
  54. pmc Stochastic modeling and simulation of the p53-MDM2/MDMX loop
    Xiaodong Cai
    Department of Electrical and Computer Engineering, University of Miami, Coral Gables, Florida 33146, USA
    J Comput Biol 16:917-33. 2009
    ..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. ncbi A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network
    Franck Toledo
    The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Cancer Cell 9:273-85. 2006
    The mechanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53DeltaP)...
  56. ncbi Isolation and identification of the human homolog of a new p53-binding protein, Mdmx
    A Shvarts
    Laboratory of Molecular Carcinogenesis, Leiden University, The Netherlands
    Genomics 43:34-42. 1997
    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...
  57. ncbi Organization, expression, and localization of the murine mdmx gene and pseudogene
    J M Parant
    Department of Molecular Genetics, Box 11, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Gene 270:277-83. 2001
    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...
  58. ncbi Chromosome mapping and sequence variation of the murine Ras effector gene Nore1
    R Yao
    Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
    Cytogenet Cell Genet 95:126-8. 2001
  59. ncbi Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets
    Arturo Chavez-Reyes
    Department of Molecular Genetics, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer Res 63:8664-9. 2003
    ..Deletion of either mdm2 or mdm4 genes, which encode p53 inhibitors, results in embryonic lethality...
  60. ncbi Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice
    Tomoo Iwakuma
    Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 23:7644-50. 2004
    Mdm2 and its homolog Mdm4 inhibit the function of the tumor suppressor p53...
  61. ncbi Mdmx as an essential regulator of p53 activity
    Jean Christophe Marine
    Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology VIB, B 9052 Ghent, Belgium
    Biochem Biophys Res Commun 331:750-60. 2005
    ..10 years ago, a search for new p53-interactors revealed the existence of an Mdm2-structurally related protein, Mdmx (or Mdm4)...
  62. ncbi Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development
    Heather A Steinman
    Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Oncogene 24:7935-40. 2005
    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...
  63. pmc Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo
    Sarah Francoz
    Laboratory For Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, Belgium
    Proc Natl Acad Sci U S A 103:3232-7. 2006
    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...
  64. ncbi MDM4 downregulates p53 transcriptional activity and response to stress during differentiation
    Sergio Menendez
    Institute of Molecular and Cell Biology, Immunos, Singapore
    Cell Cycle 10:1100-8. 2011
    ..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...
  65. ncbi Distinct roles of Mdm2 and Mdm4 in red cell production
    Marion Maetens
    Laboratory For Molecular Cancer Biology, Flanders Institute for Biotechnology VIB, University of Ghent, Belgium
    Blood 109:2630-3. 2007
    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...
  66. ncbi G alpha 12/13 basally regulates p53 through Mdm4 expression
    Mi Sung Kim
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
    Mol Cancer Res 5:473-84. 2007
    ..alpha(12/13) in cell proliferation, this study investigated the role of G alpha(12/13) in the regulation of p53 and mdm4. Immunoblotting and immunocytochemistry revealed that p53 was expressed in control embryonic fibroblasts and was ..
  67. ncbi Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis
    S Benosman
    INSERM U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Universite Louis Pasteur, Faculte de Medecine, UMRS692, Strasbourg, France
    Cell Death Differ 14:2047-57. 2007
    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...
  68. pmc Mdm2 and Mdm4 loss regulates distinct p53 activities
    Juan A Barboza
    Department of Cancer Genetics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 4095, USA
    Mol Cancer Res 6:947-54. 2008
    ..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...
  69. pmc Mdm4 loss in the intestinal epithelium leads to compartmentalized cell death but no tissue abnormalities
    Yasmine A Valentin-Vega
    Department of Genetics, Program in Genes and Development and Graduate School of Biomedical Sciences, University of Texas, M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Differentiation 77:442-9. 2009
    b>Mdm4 is a critical inhibitor of the p53 tumor suppressor. Mdm4 null mice die early during embryogenesis due to increased p53 activity...
  70. doi Regulation of MDM4 (MDMX) function by p76(MDM2): a new facet in the control of p53 activity
    S Giglio
    Institute of Neurobiology and Molecular Medicine, CNR Fondazione Santa Lucia, Roma, Italy
    Oncogene 29:5935-45. 2010
    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...
  71. pmc Turning the RING domain protein MdmX into an active ubiquitin-protein ligase
    Saravanakumar Iyappan
    Department of Biology and Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany
    J Biol Chem 285:33065-72. 2010
    The related RING domain proteins MdmX and Mdm2 are best known for their role as negative regulators of the tumor suppressor p53...
  72. pmc Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo
    Elizabeth A Slee
    The Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom
    Proc Natl Acad Sci U S A 107:19479-84. 2010
    ..This is evident from its partial rescue of embryonic lethality caused by Mdm4 deletion...
  73. pmc 14-3-3Gamma inhibition of MDMX-mediated p21 turnover independent of p53
    Jun Ho Lee
    Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 286:5136-42. 2011
    ..One of the p21 regulators is MDMX, which can directly bind to p21 and mediate its proteasomal degradation in an ubiquitination-independent fashion...
  74. ncbi Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells
    B P Zambrowicz
    Lexicon Genetics, The Woodlands, Texas 77381, USA
    Nature 392:608-11. 1998
    ..To facilitate the study of gene function on a large scale, we are using these techniques to create a library of ES cells called Omnibank, from which sequence-tagged mutations in 2,000 genes are described...