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

Publication ,  Journal Article
Matsuura, K; Huang, N-J; Cocce, K; Zhang, L; Kornbluth, S
Published in: Oncogene
March 2017

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.

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Published In

Oncogene

DOI

EISSN

1476-5594

ISSN

0950-9232

Publication Date

March 2017

Volume

36

Issue

12

Start / End Page

1698 / 1706

Related Subject Headings

  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Signal Transduction
  • Proteolysis
  • Protein Stability
  • Protein Binding
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Multiprotein Complexes
  • Humans
 

Citation

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Matsuura, K., Huang, N.-J., Cocce, K., Zhang, L., & Kornbluth, S. (2017). Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin. Oncogene, 36(12), 1698–1706. https://doi.org/10.1038/onc.2016.336
Matsuura, K., N. -. J. Huang, K. Cocce, L. Zhang, and S. Kornbluth. “Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin.Oncogene 36, no. 12 (March 2017): 1698–1706. https://doi.org/10.1038/onc.2016.336.
Matsuura K, Huang N-J, Cocce K, Zhang L, Kornbluth S. Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin. Oncogene. 2017 Mar;36(12):1698–706.
Matsuura, K., et al. “Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin.Oncogene, vol. 36, no. 12, Mar. 2017, pp. 1698–706. Epmc, doi:10.1038/onc.2016.336.
Matsuura K, Huang N-J, Cocce K, Zhang L, Kornbluth S. Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin. Oncogene. 2017 Mar;36(12):1698–1706.

Published In

Oncogene

DOI

EISSN

1476-5594

ISSN

0950-9232

Publication Date

March 2017

Volume

36

Issue

12

Start / End Page

1698 / 1706

Related Subject Headings

  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Signal Transduction
  • Proteolysis
  • Protein Stability
  • Protein Binding
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Multiprotein Complexes
  • Humans