Journal
NATURE MEDICINE
Volume 18, Issue 8, Pages 1239-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2863
Keywords
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Funding
- 'Het Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO)' scholarship
- Clare Oliver Memorial Fellowship from the Victorian Cancer Agency
- Pfizer Australia
- Victorian Endowment for Science, Knowledge and Innovation (VESKI)
- Australian National Health and Medical Research Council [509197, 1026990, 628426]
- Stand Up to Cancer
- Joint Center for Translational Medicine
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Seaver Institute
- US National Institutes of Health
- National Cancer Institute
- Association for International Cancer Research (AICR)
- Melbourne Melanoma Project
- Victorian Cancer Agency
- Belgian Foundation against Cancer
- National Health and Medical Research Council of Australia [628426] Funding Source: NHMRC
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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 (similar to 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.
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