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Published online 27 June 2005. doi:10.1083/jcb.200405112
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 15-20
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Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism

Fumihiro Higashino1, Mariko Aoyagi1, Akiko Takahashi1, Masaho Ishino2, Masato Taoka3, Toshiaki Isobe3, Masanobu Kobayashi4, Yasunori Totsuka1, Takao Kohgo1, and Masanobu Shindoh1

1 Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan
2 Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
3 Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Tokyo 192-0397, Japan
4 Institute for Genetic Medicine, Hokkaido University, Sapporo 060-8638, Japan

Correspondence to F. Higashino: fhigashi{at}den.hokudai.ac.jp


Abstract
E4orf6 plays an important role in the transportation of cellular and viral mRNAs and is known as an oncogene product of adenovirus. Here, we show that E4orf6 interacts with pp32/leucine-rich acidic nuclear protein (LANP). E4orf6 exports pp32/LANP from the nucleus to the cytoplasm with its binding partner, HuR, which binds to an AU-rich element (ARE) present within many protooncogene and cytokine mRNAs. We found that ARE-mRNAs, such as c-fos, c-myc, and cyclooxygenase-2, were also exported to and stabilized in the cytoplasm of E4orf6-expressing cells. The oncodomain of E4orf6 was necessary for both binding to pp32/LANP and effect for ARE-mRNA. C-fos mRNA was exported together with E4orf6, E1B-55kD, pp32/LANP, and HuR proteins. Moreover, inhibition of the CRM1-dependent export pathway failed to block the export of ARE-mRNAs mediated by E4orf6. Thus, E4orf6 interacts with pp32/LANP to modulate the fate of ARE-mRNAs by altering the CRM1-dependent export pathway.

F. Higashino and M. Aoyagi contributed equally to this paper.

A. Takahashi's present address is Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.

Abbreviations used in this paper: ARE, AU-rich element; BRK, baby rat kidney; COX-2, cyclooxygenase-2; LANP, leucine-rich acidic nuclear protein; LMB, leptomycin B; NES, nuclear export signal; RIP, RNP immunoprecipitation; UTR, untranslated region.


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