Title: MDM4 is a key therapeutic target in cutaneous melanoma
Authors: Gembarska, Agnieszka
Luciani, Flavie
Fedele, Clare
Russell, Elisabeth A
Dewaele, Michael
Villar, Stéphanie
Zwolinska, Aleksandra
Haupt, Sue
de Lange, Job
Yip, Dana
Goydos, James
Haigh, Jody J
Haupt, Ygal
Larue, Lionel
Jochemsen, Aart
Shi, Hubing
Moriceau, Gatien
Lo, Roger S
Ghanem, Ghanem
Shackleton, Mark
Bernal, Federico
Marine, Chris # ×
Issue Date: Jul-2012
Publisher: Nature Pub. Co.
Series Title: Nature Medicine vol:18 issue:8 pages:1239-1239
Article number: 10.1038/nm.2863
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.
ISSN: 1078-8956
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Molecular Cancer Biology
× corresponding author
# (joint) last author

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