論文

査読有り 国際誌
2021年1月

EBP2, a novel NPM‐ALK‐interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53

Molecular Oncology
  • Yuki Uchihara
  • ,
  • Kenji Tago
  • ,
  • Hiroomi Tamura
  • ,
  • Megumi Funakoshi‐Tago

15
1
開始ページ
167
終了ページ
194
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/1878-0261.12822
出版者・発行元
Wiley

The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found in anaplastic large-cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM-ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM-ALK interacted with Epstein-Barr virus nuclear antigen 1-binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM-ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0 /G1 -phase cell cycle arrest in Ba/F3 cells transformed by NPM-ALK and ALCL patient-derived Ki-JK cells, but not ALCL patient-derived SUDH-L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM-ALK and Ki-JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC-0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt-mTORC1 pathway in NPM-ALK-positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.

リンク情報
DOI
https://doi.org/10.1002/1878-0261.12822
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33040459
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782078
URL
https://onlinelibrary.wiley.com/doi/pdf/10.1002/1878-0261.12822
URL
https://onlinelibrary.wiley.com/doi/full-xml/10.1002/1878-0261.12822
ID情報
  • DOI : 10.1002/1878-0261.12822
  • ISSN : 1574-7891
  • eISSN : 1878-0261
  • PubMed ID : 33040459
  • PubMed Central 記事ID : PMC7782078

エクスポート
BibTeX RIS