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The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death

Oncogene volume 24, pages 5287–5298 (2005)Cite this article

Abstract

Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi / HtrA2. Depletion of WARTS inhibited Omi / HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi / HtrA2 both in vivo and in vitro. Activation of Omi / HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.

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Acknowledgements

We thank T Kitamura for the pMXpuro vector and Plat-E cells; Y Hata for the pClneoMyc APC expression plasmid; H Kuwahara for recombinant NE-dlg and PSD95 proteins; M Nakajima for helpful discussion; members of the Saya lab for valuable help and suggestions; and members of the Gene Technology Center at Kumamoto University for technical assistance. SK is a postdoctoral fellow of the Japan Society for the Promotion of Science (JSPS). This work was supported by the Research for the Future Program of the Japan Society for the promotion of Science and by a grant for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to HS).

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Authors and Affiliations

  1. Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Shinji Kuninaka, Masanobu Nomura, Toru Hirota, Shin-Ichi Iida, Toshihiro Hara, Shinobu Honda, Naoko Kunitoku, Takashi Sasayama, Yoshimi Arima, Tomotoshi Marumoto & Hideyuki Saya

  2. Second Department of Surgery, School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, 903-0215, Okinawa, Japan

    Kageharu Koja

  3. Institute for Virus Research, Kyoto University, Kyoto, 606-8507, Japan

    Shin Yonehara

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  1. Shinji Kuninaka
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Correspondence to Hideyuki Saya.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Kuninaka, S., Nomura, M., Hirota, T. et al. The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death. Oncogene 24, 5287–5298 (2005). https://doi.org/10.1038/sj.onc.1208682

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