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Molecular and Cellular Biology, November 2006, p. 8228-8241, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01155-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Destabilization of Interleukin-6 mRNA Requires a Putative RNA Stem-Loop Structure, an AU-Rich Element, and the RNA-Binding Protein AUF1{triangledown}

Serge Paschoud,{dagger} Afzal M. Dogar,{dagger} Catherine Kuntz, Barbara Grisoni-Neupert, Larry Richman, and Lukas C. Kühn*

Swiss Institute for Experimental Cancer Research (ISREC), Genetics Unit, CH-1066 Epalinges, Switzerland

Received 27 June 2006/ Returned for modification 1 August 2006/ Accepted 25 August 2006

Interleukin-6 mRNA is unstable and degraded with a half-life of 30 min. Instability determinants can entirely be attributed to the 3' untranslated region. By grafting segments of this region to stable green fluorescent protein mRNA and subsequent scanning mutagenesis, we have identified two conserved elements, which together account for most of the instability. The first corresponds to a short noncanonical AU-rich element. The other, 80 nucleotides further 5', comprises a sequence predicted to form a stem-loop structure. Neither element alone was sufficient to confer full instability, suggesting that they might cooperate. Overexpression of myc-tagged AUF1 p37 and p42 isoforms as well as suppression of endogenous AUF1 by RNA interference stabilized interleukin-6 mRNA. Both effects required the AU-rich instability element. Similarly, the proteasome inhibitor MG132 stabilized interleukin-6 mRNA probably through an increase of AUF1 levels. The mRNA coimmunoprecipitated specifically with myc-tagged AUF1 p37 and p42 in cell extracts but only when the AU-rich instability element was present. These results indicate that AUF1 binds to the AU-rich element in vivo and promotes IL-6 mRNA degradation.

* Corresponding author. Mailing address: Swiss Institute for Experimental Cancer Research, Genetics Unit, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 4121-692 58 36. Fax: 4121-652 69 33. E-mail: lukas.kuehn{at}isrec.ch.

{triangledown} Published ahead of print on 5 September 2006.

{dagger} S.P. and A.M.D. contributed equally to this work.

Molecular and Cellular Biology, November 2006, p. 8228-8241, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01155-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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