TY - JOUR
T1 - MDM4 is a key therapeutic target in cutaneous melanoma
AU - Gembarska, Agnieszka
AU - Luciani, Flavie
AU - Fedele, Clare
AU - Russell, Elisabeth A.
AU - Dewaele, Michael
AU - Villar, Stéphanie
AU - Zwolinska, Aleksandra
AU - Haupt, Sue
AU - de Lange, Job
AU - Yip, Dana
AU - Goydos, James
AU - Haigh, Jody J.
AU - Haupt, Ygal
AU - Larue, Lionel
AU - Jochemsen, Aart
AU - Shi, Hubing
AU - Moriceau, Gatien
AU - Lo, Roger S.
AU - Ghanem, Ghanem
AU - Shackleton, Mark
AU - Bernal, Federico
AU - Marine, Jean-Christophe
PY - 2012
Y1 - 2012
N2 - 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. © 2012 Nature America, Inc. All rights reserved.
AB - 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. © 2012 Nature America, Inc. All rights reserved.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84864677524&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/22820643
U2 - https://doi.org/10.1038/nm.2863
DO - https://doi.org/10.1038/nm.2863
M3 - Article
C2 - 22820643
SN - 1078-8956
VL - 18
SP - 1239
EP - 1247
JO - Nature medicine
JF - Nature medicine
IS - 8
ER -