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.

journal_name

Mol Cell Biol

authors

Matijasevic Z,Steinman HA,Hoover K,Jones SN

doi

10.1128/MCB.01108-07

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

1265-73

issue

4

eissn

0270-7306

issn

1098-5549

pii

MCB.01108-07

journal_volume

28

pub_type

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