Active Ras signaling is involved in the transcriptional upregulation of the functional p53 inhibitor MDM4 in human and murine hepatocellular carcinoma

MDM4 is a p53 binding protein that negatively regulates p53-dependent transcription. MDM4 was found overexpressed in a variety of human cancers and amplifications of the MDM4 gene locus were reported with high frequency in most of the tumors analyzed. We have previously demonstrated that MDM4 is upregulated in about 50% of human hepatocellular carcinomas (HCC), both at messenger RNA and protein level. Although we identified 1q32 gain as a mechanism leading to MDM4 overexpression in human HCCs, many liver tumors display a balanced MDM4 gene locus. Thus, additional mechanisms are responsible for MDM4 aberrant expr…