MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4.

Abstract:

:Murine double minute (MDM2) binding protein (MTBP) has been implicated in cancer progression. Here, we demonstrate one mechanism by which MTBP inhibits cancer metastasis. Overexpression of MTBP in human osteosarcoma cell lines lacking wild-type p53 did not alter primary tumor growth in mice, but significantly inhibited metastases. MTBP downregulation increased the migratory potential of MDM2(-/-)p53(-/-) mouse embryonic fibroblasts, suggesting that MTBP inhibited cell migration independently of the Mdm2-p53 pathway. Co-immunoprecipitation and mass spectrometric analysis identified alpha-actinin-4 (ACTN4) as an MTBP-interacting protein. Endogenous MTBP interacted with and partially colocalized with ACTN4. MTBP overexpression inhibited cell migration and filopodia formation mediated by ACTN4. Increased cell migration by MTBP downregulation was inhibited by concomitant downregulation of ACTN4. MTBP also inhibited ACTN4-mediated F-actin bundling. We furthermore demonstrated that nuclear localization of MTBP was dispensable for inhibiting ACTN4-mediated cell migration and filopodia formation. Thus, MTBP suppresses cell migration, at least partially, by inhibiting ACTN4 function. Our study not only provides a mechanism of metastasis suppression by MTBP, but also suggests MTBP as a potential biomarker for cancer progression.

journal_name

Oncogene

journal_title

Oncogene

authors

Agarwal N,Adhikari AS,Iyer SV,Hekmatdoost K,Welch DR,Iwakuma T

doi

10.1038/onc.2012.69

subject

Has Abstract

pub_date

2013-01-24 00:00:00

pages

462-70

issue

4

eissn

0950-9232

issn

1476-5594

pii

onc201269

journal_volume

32

pub_type

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