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Molecular and Cellular Biology, June 2004, p. 4835-4847, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4835-4847.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Distinct Domains of AU-Rich Elements Exert Different Functions in mRNA Destabilization and Stabilization by p38 Mitogen-Activated Protein Kinase or HuR

Reinhard Winzen,1,{dagger} Gayatri Gowrishankar,1,{dagger} Frank Bollig,2,{ddagger} Natalie Redich,1 Klaus Resch,2 and Helmut Holtmann1*

Institute of Biochemistry,1 Institute of Pharmacology, Medical School Hannover, D-30625 Hannover, Germany2

Received 21 November 2003/ Returned for modification 18 December 2003/ Accepted 12 March 2004

AU-rich elements (AREs) control the expression of numerous genes by accelerating the decay of their mRNAs. Rapid decay and deadenylation of ß-globin mRNA containing AU-rich 3' untranslated regions of the chemoattractant cytokine interleukin-8 (IL-8) are strongly attenuated by activating the p38 mitogen-activated protein (MAP) kinase/MAP kinase-activated protein kinase 2 (MK2) pathway. Further evidence for a crucial role of the poly(A) tail is provided by the loss of destabilization and kinase-induced stabilization in ARE RNAs expressed as nonadenylated forms by introducing a histone stem-loop sequence. The minimal regulatory element in the IL-8 mRNA is located in a 60-nucleotide evolutionarily conserved sequence with a structurally and functionally bipartite character: a core domain with four AUUUA motifs and limited destabilizing function on its own and an auxiliary domain that markedly enhances destabilization exerted by the core domain and thus is essential for the rapid removal of RNA targets. A similar bipartite structure and function are observed for the granulocyte-macrophage colony-stimulating factor (GM-CSF) ARE. Stabilization in response to p38/MK2 activation is seen with the core domain alone and also after mutation of the AUUUA motifs in the complete IL-8 ARE. Stabilization by ARE binding protein HuR requires different sequence elements. Binding but no stabilization is observed with the IL-8 ARE. Responsiveness to HuR is gained by exchanging the auxiliary domain of the IL-8 ARE with that of GM-CSF or with a domain of the c-fos ARE, which results in even stronger responsiveness. These results show that distinct ARE domains differ in function with regard to destabilization, stabilization by p38/MK2 activation, and stabilization by HuR.

* Corresponding author. Mailing address: Institute of Biochemistry, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Phone: (49) 511-5323384. Fax: (49) 511-5322827. E-mail: holtmann.helmut{at}mh-hannover.de.

{dagger} R.W. and G.G. contributed equally to this work.

{ddagger} Present address: Biocenter, University of Wuerzburg, Physiological Chemistry I, D-97074 Wuerzburg, Germany.

Molecular and Cellular Biology, June 2004, p. 4835-4847, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4835-4847.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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