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Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins

Oncogene volume 22, pages 6919–6927 (2003)Cite this article

Abstract

The adenovirus E4orf6 is a viral oncoprotein known to cooperate with the E1A gene product in transforming primary murine cells. It has been shown to inhibit the apoptotic activities of p53 and p73 through direct binding to these proteins. Here, we demonstrate that the adenovirus E4orf6 protein inhibits apoptosis mediated by BNIP3 and Bik, which are BH3-only proteins of the Bcl-2 family. This activity was not mediated by p53 and p73 because E4orf6 had the same effect on the apoptosis in Saos-2 cells that do not express p53-related genes. It was also ascertained that E4orf6 could change the mitochondrial localization of BNIP3 and Bik. A mutant lacking the nuclear export signal of E4orf6 failed to inhibit apoptosis and to translocate BNIP3 protein from the mitochondria. Moreover, it was also established that E4orf6 was able to interact with BNIP3 and Bik. In BNIP3 protein, the region required for the interaction included the transmembrane domain, which is required for the localization of BNIP3 to the mitochondria. These results suggest that E4orf6 is exported from the nucleus to the cytoplasm, enabling it to interact with BH3-only proteins, eventually leading to the inhibition of apoptotic activity.

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Acknowledgements

We thank G Chinnadurai for BNIP3 plasmid, T Shenk for the antibody for E4orf6 (RSA♯3) and E4orf6 plasmid and I Matsuoka for technical support. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and by a Grant-in Aid from the Akiyama Foundation.

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Authors and Affiliations

  1. Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, N13, W7, Kita-ku, Sapporo, 060-8586, Japan

    Mariko Aoyagi, Fumihiro Higashino, Motoaki Yasuda, Akiko Takahashi, Yasunori Totsuka, Takao Kohgo & Masanobu Shindoh

  2. Department of Oral Health Science, Hokkaido University Graduate School of Dental Medicine, N13, W7, Kita-Ku, Sapporo, 060-8586, Japan

    Mariko Aoyagi, Akiko Takahashi & Hidehiko Sano

  3. Department of Biology, Hokkaido Institute of Public Health, Sapporo, 060-0819, Japan

    Yukiharu Sawada

  4. Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan

    Masanobu Kobayashi

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  1. Mariko Aoyagi
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Correspondence to Fumihiro Higashino.

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Aoyagi, M., Higashino, F., Yasuda, M. et al. Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins. Oncogene 22, 6919–6927 (2003). https://doi.org/10.1038/sj.onc.1206743

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