Nuclear export of adenovirus e4orf6 protein is necessary for its ability to antagonize apoptotic activity of bh3-only proteins

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. Access through your institution Buy or subscribe This is a preview of subscription content,

access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn

more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS

OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LINC COMPLEX PROTEIN NESPRIN-2 HAS PRO-APOPTOTIC

ACTIVITY VIA BCL-2 FAMILY PROTEINS Article Open access 15 January 2024 AUTOPHAGY-COMPETENT MITOCHONDRIAL TRANSLATION ELONGATION FACTOR TUFM INHIBITS CASPASE-8-MEDIATED APOPTOSIS Article

Open access 12 September 2021 MAREK’S DISEASE VIRUS MEQ ONCOPROTEIN INTERACTS WITH CHICKEN HDAC 1 AND 2 AND MEDIATES THEIR DEGRADATION VIA PROTEASOME DEPENDENT PATHWAY Article Open access 12

January 2021 REFERENCES * Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstron S, Avery BJ, Ebb RG, Subramanian T, Chittenden T, Luts RJ and Chinnadurai G . (1995). _Oncogene_, 11,

1921–1928. * Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C and Chinnanurai G . (1994). _Cell_, 79, 341–351. * Chandar N, Billig B, McMaster J

and Nozak J . (1992). _Br. J. Cancer_, 65, 208–214. * Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, Saxena S, Gietz RD and Greenberg AH . (1997). _J. Exp. Med._, 186, 1975–1983. *

Cizeau J, Ray R, Chen G, Gietz RD and Greenberg AH . (2000). _Oncogene_, 19, 5453–5463. * Dobbelstein M, Roth J, Kimberly WT, Levine AJ and Shenk T . (1997). _EMBO J._, 16, 4276–4284. *

Dobner T, Horikoshi N, Rubenwolf S and Shenk T . (1996). _Science_, 272, 1470–1473. * Dosch T, Horn F, Schneider G, Kratzer F, Dobner T, Hauber J and Stauber RH . (2001). _J. Virol._, 75,

5677–5683. * Fischer N, Voss MD, Mueller-Lantzsch N and Grasser FA . (1999). _FEBS Lett._, 447, 311–314. * Goodrum FD, Shenk T and Ornelles DA . (1996). _J. Virol._, 70, 6323–6335. * Green

DR and Reed JC . (1998). _Science_, 281, 1309–1312. * Gross A, McDonnell JM and Korsmeyer SJ . (1999). _Genes Dev._, 13, 1899–1911. * Halbert DN, Cutt JR and Shenk T . (1985). _J. Virol._,

56, 250–257. * Harlow E, Whyte P, Franza R and Schley C . (1986). _Mol. Cell. Biol._, 6, 1579–1589. * Higashino F, Pipas JM and Shenk T . (1998). _Proc. Natl. Acad. Sci. USA_, 95,

15683–15687. * Huang DC and Strasser A . (2000). _Cell_, 103, 839–842. * Ishida S, Yamashita Y, Nakaya U and Tokino T . (2000). _Jpn. J. Cancer Res._, 91, 174–180. * Kaghad M, Bonnet H, Yang

A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F and Caput D . (1997). _Cell_, 90, 809–819. * Kim JY, Cho JJ, Ha J and Park JH . (2002).

_Arch. Biochem. Biophys._, 398, 147–152. * Kubasiak LA, Hernandez OM, Bishopric NH and Webster KA . (2002). _Proc. Natl. Acad. Sci. USA_, 99, 12825–12830. * Marton MJ, Baim SB, Ornelles DA

and Shenk T . (1990). _J. Virol._, 64, 2345–2359. * Miyashita T and Reed JC . (1995). _Cell_, 80, 293–239. * Moore M, Horikoshi N and Shenk T . (1996). _Proc. Natl. Acad. Sci. USA_, 93,

11295–11301. * Nakano K and Vousden KH . (2001). _Mol. Cell_, 7, 683–694. * Nevels M, Rubenwolf S, Spruss T, Wolf H and Dobner T . (1997). _Proc. Natl. Acad. Sci. USA_, 94, 1206–1211. *

Nevels M, Rubenwolf S, Spruss T, Wolf H and Dobner T . (2000). _J. Virol._, 74, 5168–5181. * Nevels M, Spruss T, Wolf H and Dobner T . (1998). _Oncogene_, 18, 9–17. * Oda E, Ohki R, Murasawa

H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N . (2000). _Science_, 288, 1053–1058. * Orlando JS and Ornelles DA . (1999). _J. Virol._, 73, 4600–4610. * Querido E,

Blanchette P, Yan Q, Kamura T, Morrison M, Boivin D, Kaelin WG, Conaway RC, Conaway JW and Branton PE . (2001). _Genes Dev._, 15, 3104–3117. * Querido E, Marcellus RC, Lai A, Charbnneau R,

Teodoro JG, Ketner G and Branton PE . (1997). _J. Virol._, 71, 3788–3798. * Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Giets RD and Greenberg AH . (2000). _J. Biol. Chem._,

275, 1439–1448. * Reed JC . (1995). _J. Cell. Biol._, 124, 1–6. * Sarnow P, Hearing P, Anderson CW, Halbert DN, Shenk T and Levine AJ . (1984). _J. Virol._, 49, 692–700. * Sarnow P, Ho YS,

Williams J and Levine AJ . (1982). _Cell_, 28, 387–394. * Steegenga WT, Riteco N, Jochemsen AG, Fallanx FJ and Bos JL . (1998). _Oncogene_, 16, 349–357. * Teodoro JG and Branton PE . (1997).

_J. Virol._, 71, 1739–1746. * Tsujimoto Y and Shimizu S . (2000). _FEBS Lett._, 466, 6–10. * Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R and Greenberg AH .

(2000). _Mol. Cell. Biol._, 20, 5454–5468. * Weigel S and Dobbelstein M . (2000). _J. Virol._, 74, 764–772. * Weinberg DH and Ketner G . (1986). _J. Virol._, 57, 833–838. * Yasuda M,

Theodrakis P, Subramanian T and Chinnadurai G . (1998). _J. Biol. Chem._, 273, 12415–12421. * Yu J, Zhang L, Hwang PM, Kinzler KW and Vogelstein B . (2001). _Mol. Cell_, 7, 673–682. Download

references 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. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * 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 * 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 * Department of Biology, Hokkaido Institute of Public Health, Sapporo,

060-0819, Japan Yukiharu Sawada * Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan Masanobu Kobayashi Authors

* Mariko Aoyagi View author publications You can also search for this author inPubMed Google Scholar * Fumihiro Higashino View author publications You can also search for this author

inPubMed Google Scholar * Motoaki Yasuda View author publications You can also search for this author inPubMed Google Scholar * Akiko Takahashi View author publications You can also search

for this author inPubMed Google Scholar * Yukiharu Sawada View author publications You can also search for this author inPubMed Google Scholar * Yasunori Totsuka View author publications You

can also search for this author inPubMed Google Scholar * Takao Kohgo View author publications You can also search for this author inPubMed Google Scholar * Hidehiko Sano View author

publications You can also search for this author inPubMed Google Scholar * Masanobu Kobayashi View author publications You can also search for this author inPubMed Google Scholar * Masanobu

Shindoh View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Fumihiro Higashino. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 23 April 2002 * Revised: 28 April 2003 *

Accepted: 28 April 2003 * Published: 09 October 2003 * Issue Date: 09 October 2003 * DOI: https://doi.org/10.1038/sj.onc.1206743 SHARE THIS ARTICLE Anyone you share the following link with

will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative KEYWORDS * E4orf6 * adenovirus * nuclear export * BH-3 only protein * BNIP3 * Bik