MdmX regulates transformation and chromosomal stability in p53-deficient cells

Abstract

The cellular homologues Mdm2 and MdmX play critical roles in regulating the activity of the p53 tumor suppressor in damaged and non-damaged cells and during development in mice. Recently, we have utilized genetically defined primary cells and mice to reveal that endogenous levels of MdmX can also suppress multipolar mitosis and transformation in hyperploid p53-deficient cells and tumorigenesis in p53-deficient mice. These MdmX functions are not shared by Mdm2, and are distinct from the well-established ability of MdmX to complex with and inhibit p53 activity. Here we discuss some of the ramifications of MdmX loss in p53-deficient cells and mice, and we explore further the fate of MdmX/ p53-double null embryonic fibroblasts undergoing multi-polar cell division using time-lapse video microscopy. We also discuss the relationship between chromosomal loss, cell proliferation, and the tumorigenic potential of p53-deficient cells lacking MdmX.

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

“…In this study, we proposed that a reason why a cancer cell would not retain the oncogenic activity of HDMX is because it has already inhibited p53 signaling by mutations of other key regulatory genes in the pathway and, therefore, the cell is no longer under selective pressure to sustain higher levels of HDMX. Furthermore, cells with deficient p53 activity could be under positive selection pressure to reduce HDMX levels as suggested by 2 recent studies, which report that full-length MDMX functions as a tumor suppressor in cells with deficient p53 function (41,42). Indeed, our observations made in 3 cell panels, comprising a total of 115 different cell lines, lend support to this model.…”

RNAi knock of HdmX or Hdm2 leads to new insights into p53 signaling

“…This appears to be in contrast to in vivo studies where the knockout of Mdm2 or MdmX in adult mouse tissues led to non-overlapping roles in regards to the regulation of p53 activity. 11 It is possible that the impact of overexpression of Hdm2 and HdmX in human tumors maybe limited to inhibiting p53; however, results suggesting the presence of p53-independent effects of MdmX 12 imply the existence of novel roles for HdmX that were not uncovered in this gene expression study.…”

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

“…These effects appeared to be at least partially p53-independent. This study, together with previous reports, 25,26 suggests a role of MdmX that stretches beyond p53 inhibition.…”