MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma

Atul Ranjan, Swathi V. Iyer, Christopher Ward, Tim Link, Francisco J. Diaz, Animesh Dhar, Ossama W. Tawfik, Steven A. Weinman, Yoshiaki Azuma, Tadahide Izumi, Tomoo Iwakuma

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the prognosis of HCC patients, especially those with metastasis, remains extremely poor. This is partly due to unclear molecular mechanisms underlying HCC metastasis. Our previous study indicates that MDM2 Binding Protein (MTBP) suppresses migration and metastasis of HCC cells. However, signaling pathways regulated by MTBP remain unknown. To identify metastasis-associated signaling pathways governed by MTBP, we have performed unbiased luciferase reporter-based signal array analyses and found that MTBP suppresses the activity of the ETS-domain transcription factor Elk-1, a downstream target of Erk1/2 MAP kinases. MTBP also inhibits phosphorylation of Elk-1 and decreases mRNA expression of Elk-1 target genes. Reduced Elk-1 activity is caused by inhibited nuclear translocation of phosphorylated Erk1/2 (p-Erk) by MTBP and subsequent inhibition of Elk-1 phosphorylation. We also reveal that MTBP inhibits the interaction of p-Erk with importin-7/RanBP7 (IPO7), an importin family member which shuttles p-Erk into the nucleus, by binding to IPO7. Moreover, high levels of MTBP in human HCC tissues are correlated with cytoplasmic localization of p-Erk1/2. Our study suggests that MTBP suppresses metastasis, at least partially, by downmodulating the Erk1/2-Elk-1 signaling pathway, thus identifying a novel regulatory mechanism of HCC metastasis by regulating the subcellular localization of p-Erk.

Original languageEnglish
Pages (from-to)21429-21443
Number of pages15
JournalOncotarget
Volume9
Issue number30
DOIs
StatePublished - Apr 20 2018

Bibliographical note

Publisher Copyright:
© Ranjan et al.

Funding

We thank Danny R. Welch, Alejandro Parrales, Satomi Yamamoto, Elizabeth Thoenen, and Liver Center at KUMC for technical assistance, helpful discussion, providing human tissues, and editing the manuscript.This project is supported by NIH R01-CA174735 (T.I.), P30-CA168524 (R.A.J.), and Children's Mercy Big Slick KC grants.

FundersFunder number
Children's Mercy Big Slick KC
NIH R01-CA174735
T.I.
National Institutes of Health (NIH)R01-CA174735
National Childhood Cancer Registry – National Cancer InstituteP30CA168524
University of Kansas Medical Center

    Keywords

    • Elk-1
    • Erk1/2
    • MDM2
    • MTBP
    • Metastasis

    ASJC Scopus subject areas

    • Oncology

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