| First Author | Gembarska A | Year | 2012 |
| Journal | Nat Med | Volume | 18 |
| Issue | 8 | Pages | 1239-47 |
| PubMed ID | 22820643 | Mgi Jnum | J:317304 |
| Mgi Id | MGI:6852401 | Doi | 10.1038/nm.2863 |
| Citation | Gembarska A, et al. (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18(8):1239-47 |
| abstractText | 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 ( approximately 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. |
