MdmX Promotes Bipolar Mitosis To Suppress Transformation and Tumorigenesis in p53-Deficient Cells and Mice

Abstract

Mdm2 and MdmX are structurally related p53-binding proteins that function as critical negative regulators of p53 activity in embryonic and adult tissue. The overexpression of Mdm2 or MdmX inhibits p53 tumor suppressor functions in vitro, and the amplification of Mdm2 or MdmX is observed in human cancers retaining wild-type p53. We now demonstrate a surprising role for MdmX in suppressing tumorigenesis that is distinct from its oncogenic ability to inhibit p53. The deletion of MdmX induces multipolar mitotic spindle formation and the loss of chromosomes from hyperploid p53-null cells. This reduction in chromosome number, not observed in p53-null cells with Mdm2 deleted, correlates with increased cell proliferation and the spontaneous transformation of MdmX/p53-null mouse embryonic fibroblasts in vitro and with an increased rate of spontaneous tumorigenesis in MdmX/p53-null mice in vivo. These results indicate that MdmX has a p53-independent role in suppressing oncogenic cell transformation, proliferation, and tumorigenesis by promoting centrosome clustering and bipolar mitosis.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank Gayle Pageau, Meg Byron, and Jeannie Lawrence for their advice on chromosomal staining; Marilyn Keeler and Phil Bilderback for technical assistance with the cell culture assays; Charlene Baron for assistance with manuscript preparation; and Greenfield Sluder for helpful comments on the manuscript. We also thank Mark Jackson (Lerner Research Institute, Case Western Reserve University) for providing us with the MdmX expression construct.

Core facilities were supported by program project grant 5P30DK32520 from the National Institute of Diabetes and Digestive and Kidney Diseases. This work was supported by a grant from the National Institutes of Health to S.N.J. (RO1CA77735).