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J. Biol. Chem., Vol. 283, Issue 6, 3191-3199, February 8, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/6/3191    most recent M705575200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Skinner, S. J. Articles by Brooks, S. A. Search for Related Content PubMed PubMed Citation Articles by Skinner, S. J. Articles by Brooks, S. A. Social Bookmarking                      What's this?

Extracellular Signal-regulated Kinase Regulation of Tumor Necrosis Factor- mRNA Nucleocytoplasmic Transport Requires TAP-NxT1 Binding and the AU-rich Element^*

Stephen J. Skinner, Kristen M. Deleault, Ryan Fecteau, and Seth A. Brooks^¶1

From the Veterans Affairs Medical Center, White River Junction, Vermont 05009 and the Department of Medicine, Dartmouth Medical School, and the ^¶Department of Microbiology and Immunology, Dartmouth College, Lebanon, New Hampshire 03756

Tumor necrosis factor- (TNF-) production is regulated by transcriptional and posttranscriptional mechanisms. Lipopolysaccharide activates the NFB pathway increasing TNF- transcription. Lipopolysaccharide also activates the mitogen-activated protein kinase pathways, resulting in stabilization and enhanced translation of the TNF- message. In addition, nuclear export of the TNF- mRNA is a posttranscriptionally regulated process involving the Tpl2-ERK pathway and requiring the presence of the TNF- AU-rich element (ARE). We demonstrate that nuclear export of the TNF- message requires not only the TNF- ARE but also the interaction of the proteins TAP and NxT1, both of which are involved in nucleocytoplasmic transport of mRNA. Through the use of dominant negative ERK1 and ERK2, we establish that control of TNF- mRNA nuclear export operates specifically through ERK1. Finally, we examined the role of two established TNF- ARE-binding proteins, HuR and tristetraprolin, that shuttle between the nucleus and cytoplasm. These data demonstrate that neither tristetraprolin nor HuR is required for TNF- mRNA export. It is unclear at this time if ARE-binding protein(s) directly interact with the TAP-NxT1 complex, if each complex is independently targeted by ERK1, or if only one complex is targeted.

Received for publication, July 6, 2007 , and in revised form, November 28, 2007.

^* This work was supported by a Merit Award (to S. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence and reprint requests should be addressed: Dr. Seth Brooks, Veterans Administration Medical Center, Research (151), 215 N. Main St., White River Junction, VT 05009. Tel.: 802-295-9363 (ext. 5616); Fax: 802-296-6308; E-mail: seth.brooks{at}dartmouth.edu.

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