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Nat Med. 2012 Aug;18(8):1239-47. doi: 10.1038/nm.2863. Epub 2012 Jul 22.

MDM4 is a key therapeutic target in cutaneous melanoma.

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1
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.

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.

PMID:
22820643
PMCID:
PMC3744207
DOI:
10.1038/nm.2863
[Indexed for MEDLINE]
Free PMC Article

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