Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Oncogene. 2013 Jan 24;32(4):462-70. doi: 10.1038/onc.2012.69. Epub 2012 Feb 27.
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.
鼠双微体 2 结合蛋白（MDM2BP）已被牵连到癌症的进展中。在这里，我们展示了 MTBP 抑制癌症转移的一种机制。在缺乏野生型 p53 的人骨肉瘤细胞系中过表达 MTBP 不会改变小鼠中的原发性肿瘤生长，但显著抑制了转移。MTBP 的下调增加了 MDM2(-/-)p53(-/-) 小鼠胚胎成纤维细胞的迁移潜力，这表明 MTBP 抑制细胞迁移不依赖于 Mdm2-p53 途径。免疫共沉淀和质谱分析鉴定出 α-辅肌动蛋白 4（ACTN4）是 MTBP 的相互作用蛋白。内源性 MTBP 与 ACTN4 相互作用，并部分共定位。MTBP 的过表达抑制了 ACTN4 介导的细胞迁移和片状伪足的形成。MTBP 下调增加的细胞迁移可通过同时下调 ACTN4 来抑制。MTBP 还抑制了 ACTN4 介导的 F-肌动蛋白束。我们还证明，MTBP 的核定位对于抑制 ACTN4 介导的细胞迁移和片状伪足的形成是不必要的。因此，MTBP 通过抑制 ACTN4 的功能至少部分地抑制细胞迁移。我们的研究不仅提供了 MTBP 抑制转移的机制，而且还表明 MTBP 可能是癌症进展的潜在生物标志物。
