title: MDM4 is a key therapeutic target in cutaneous melanoma.
abstract: The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.
authors: Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium; Center for Human Genetics, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.
authors: Agnieszka
authors: A
authors: Gembarska
authors: Flavie
authors: F
authors: Luciani
authors: Clare
authors: C
authors: Fedele
authors: Elisabeth A
authors: EA
authors: Russell
authors: Michael
authors: M
authors: Dewaele
authors: Stéphanie
authors: S
authors: Villar
authors: Aleksandra
authors: A
authors: Zwolinska
authors: Sue
authors: S
authors: Haupt
authors: Job
authors: J
authors: de Lange
authors: Dana
authors: D
authors: Yip
authors: James
authors: J
authors: Goydos
authors: Jody J
authors: JJ
authors: Haigh
authors: Ygal
authors: Y
authors: Haupt
authors: Lionel
authors: L
authors: Larue
authors: Aart
authors: A
authors: Jochemsen
authors: Hubing
authors: H
authors: Shi
authors: Gatien
authors: G
authors: Moriceau
authors: Roger S
authors: RS
authors: Lo
authors: Ghanem
authors: G
authors: Ghanem
authors: Mark
authors: M
authors: Shackleton
authors: Federico
authors: F
authors: Bernal
authors: Jean-Christophe
authors: JC
authors: Marine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor / Q000378:metabolism / Q000637:transplantation; D057846:Cell-Penetrating Peptides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000737:chemistry* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000209:etiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000737:chemistry*; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D057846:Cell-Penetrating Peptides; C482775:MDM4 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C583866:SAH-p53-8 peptide; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human