par 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 Elias 
;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe
Référence Nature medicine, 18, page (1239-1247)
Publication Publié, 2012-07
;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe Référence Nature medicine, 18, page (1239-1247)
Publication Publié, 2012-07
Article révisé par les pairs
| Résumé : | 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. |
