論文

査読有り
2017年3月

Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin

ONCOGENE
  • K. Matsuura
  • ,
  • N-J Huang
  • ,
  • K. Cocce
  • ,
  • L. Zhang
  • ,
  • S. Kornbluth

36
12
開始ページ
1698
終了ページ
1706
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/onc.2016.336
出版者・発行元
NATURE PUBLISHING GROUP

Evasion of apoptosis allows many cancers to resist chemotherapy. Apoptosis is mediated by the serial activation of caspase family proteins. These proteases are often activated upon the release of cytochrome c from the mitochondria, which is promoted by the proapoptotic Bcl-2 family protein, Bax. This function of Bax is enhanced by the MOAP-1 (modulator of apoptosis protein 1) protein in response to DNA damage. Previously, we reported that MOAP-1 is targeted for ubiquitylation and degradation by the APC/CCdh1 ubiquitin ligase. In this study, we identify the HECT (homologous to the E6-AP carboxyl terminus) family E3 ubiquitin ligase, UBR5, as a novel ubiquitin ligase for MOAP-1. We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells. In addition, we show that Dyrk2 kinase, a reported UBR5 interactor, cooperates with UBR5 in mediating MOAP-1 ubiquitylation. Importantly, we found that cisplatin-resistant ovarian cancer cell lines exhibit lower levels of MOAP-1 accumulation than their sensitive counterparts upon cisplatin treatment, consistent with the previously reported role of MOAP-1 in modulating cisplatin-induced apoptosis. Accordingly, UBR5 knockdown increased MOAP-1 expression, enhanced Bax activation and sensitized otherwise resistant cells to cisplatin-induced apoptosis. Furthermore, UBR5 expression was higher in ovarian cancers from cisplatin-resistant patients than from cisplatin-responsive patients. These results show that UBR5 downregulates proapoptotic MOAP-1 and suggest that UBR5 can confer cisplatin resistance in ovarian cancer. Thus UBR5 may be an attractive therapeutic target for ovarian cancer treatment.

Web of Science ® 被引用回数 : 30

リンク情報
DOI
https://doi.org/10.1038/onc.2016.336
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/27721409
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447866
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000397460600009&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/27721409
URL
http://orcid.org/0000-0003-4612-6031
ID情報
  • DOI : 10.1038/onc.2016.336
  • ISSN : 0950-9232
  • eISSN : 1476-5594
  • ORCIDのPut Code : 45673951
  • PubMed ID : 27721409
  • PubMed Central 記事ID : PMC5447866
  • Web of Science ID : WOS:000397460600009

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