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  • Original Paper
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UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination

Oncogene volume 24, pages 7156–7169 (2005)Cite this article

Abstract

p73 protein level is kept extremely low in mammalian cultured cells and its stability may be regulated by not only the ubiquitin/proteasome-dependent proteolysis but also through other unidentified mechanisms. Here, we found for the first time that p73 is physically as well as functionally associated with the U-box-type E3/E4 ubiquitin ligase UFD2a. The immunoprecipitation experiments demonstrated that this interaction is mediated by the COOH-terminal region of p73α containing SAM domain. During the cisplatin-induced apoptosis in SH-SY5Y neuroblastoma cells, p73α accumulated at a protein level, whereas the endogenous UFD2a was significantly reduced in response to cisplatin. Ectopic expression of UFD2a decreased the half-life of p73α in association with a significant inhibition of the p73α-mediated transactivation as well as proapoptotic activity. Downregulation of endogenous UFD2a by antisense strategy resulted in a remarkable accumulation of p73α. Unexpectedly, UFD2a-mediated degradation of p73α was sensitive to the proteasomal inhibitor, however, UFD2a did not affect the ubiquitination levels of p73α. Taken together, our present findings imply that UFD2a might promote the proteasomal turnover of p73 in a ubiquitination-independent manner, and also suggest that UFD2a might play an important role in the regulation of cisplatin-induced apoptosis mediated by p73.

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Acknowledgements

We are grateful to Dr KI Nakayama for providing us with mammalian expression plasmid for FLAG-tagged mouse UFD2a and Ms Y Nakamura for assistance with DNA sequencing. This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare for Third Term Comprehensive Control Research for Cancer, a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science.

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  1. Mitsuchika Hosoda and Toshinori Ozaki: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, 260- 8717, Chiba, Japan

    Mitsuchika Hosoda, Toshinori Ozaki, Kou Miyazaki, Syunji Hayashi, Kazushige Furuya, Takayuki Hanamoto & Akira Nakagawara

  2. Department of General Surgery, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan

    Mitsuchika Hosoda, Syunji Hayashi, Ken-ichi Watanabe, Takahito Nakagawa & Satoru Todo

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  1. Mitsuchika Hosoda
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Correspondence to Akira Nakagawara.

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Hosoda, M., Ozaki, T., Miyazaki, K. et al. UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination. Oncogene 24, 7156–7169 (2005). https://doi.org/10.1038/sj.onc.1208872

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