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.
Nat Med. 2012 Aug;18(8):1239-47. doi: 10.1038/nm.2863. Epub 2012 Jul 22.
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.
p53 肿瘤抑制途径的失活，通常通过 TP53（编码肿瘤蛋白 53）的突变发生，是人类癌症中的一个常见步骤。然而，在黑色素瘤——一种高度化疗耐药的疾病中——TP53 突变罕见，这增加了这种癌症可能使用替代方法来克服 p53 介导的肿瘤抑制的可能性。在这里，我们表明 Mdm4 p53 结合蛋白同源物（MDM4），一种 p53 的负调节剂，在相当大比例（约 65%）的 I-IV 期人类黑色素瘤中上调，并且黑素细胞特异性 Mdm4 过表达增强了由致癌基因 Nras 诱导的黑色素瘤小鼠模型中的肿瘤发生。MDM4 通过拮抗 p53 促凋亡功能促进人类转移性黑色素瘤的存活。值得注意的是，抑制 MDM4-p53 相互作用恢复了黑色素瘤细胞中的 p53 功能，导致对细胞毒性化疗和 BRAF（V600E）致癌基因抑制剂的敏感性增加。我们的研究结果将 MDM4 鉴定为人类黑色素瘤中 p53 功能受损的关键决定因素，并将 MDM4 指定为抗黑色素瘤联合治疗的有希望的靶点。
