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Molecular and Cellular Biology, May 2003, p. 3506-3515, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3506-3515.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Constitutive Decay Element Promotes Tumor Necrosis Factor Alpha mRNA Degradation via an AU-Rich Element-Independent Pathway

Georg Stoecklin,{dagger} Min Lu, Bernd Rattenbacher, and Christoph Moroni*

Institute of Medical Microbiology, University of Basel, 4003 Basel, Switzerland

Received 5 November 2002/ Returned for modification 12 December 2002/ Accepted 18 February 2003

Tumor necrosis factor alpha (TNF-{alpha}) expression is regulated by transcriptional as well as posttranscriptional mechanisms, the latter including the control of mRNA decay through an AU-rich element (ARE) in the 3' untranslated region (UTR). Using two mutant cell lines deficient for ARE-mediated mRNA decay, we provide evidence for a second element, the constitutive decay element (CDE), which is also located in the 3' UTR of TNF-{alpha}. In stably transfected RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS), the CDE continues to target a reporter transcript for rapid decay, whereas ARE-mediated decay is blocked. Similarly, the activation of p38 kinase and phosphatidylinositol 3-kinase in NIH 3T3 cells inhibits ARE-mediated but not CDE-mediated mRNA decay. The CDE was mapped to an 80-nucleotide (nt) segment downstream of the ARE, and point mutation analysis identified within the CDE a conserved sequence of 15 nt that is required for decay activity. We propose that the CDE represses TNF-{alpha} expression by maintaining the mRNA short-lived, thereby preventing excessive induction of TNF-{alpha} after LPS stimulation. Thus, CDE-mediated mRNA decay is likely to be an important mechanism limiting LPS-induced pathologic processes.

* Corresponding author. Mailing address: Christoph Moroni Institute of Medical Microbiology, University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland. Phone: 41 61 267 32 64. Fax: 41 61 267 32 83. E-mail: christoph.moroni{at}unibas.ch.

{dagger} Present address: Division of Rheumatology and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

Molecular and Cellular Biology, May 2003, p. 3506-3515, Vol. 23, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.10.3506-3515.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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