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PMID: 12724409 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A constitutive decay element promotes tumor necrosis factor alpha mRNA degradation via an AU-rich element-independent pathway.

Molecular and cellular biology ·Vol. 23 ·No. 10 ·2003-05-00 ·Pages 3506-15

Stoecklin G, Lu M, Rattenbacher B, Moroni C

Abstract

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.

MeSH Terms
3' Untranslated Regions 3T3 Cells Animals Base Sequence Blotting, Northern Dactinomycin/pharmacology Gene Deletion Gene Expression Regulation Genes, Reporter Granulocyte-Macrophage Colony-Stimulating Factor/metabolism Green Fluorescent Proteins Humans Luminescent Proteins/metabolism Macrophages/metabolism Mice Mitogen-Activated Protein Kinases/metabolism Models, Genetic Molecular Sequence Data Phosphatidylinositol 3-Kinases/metabolism Plasmids/metabolism Point Mutation RNA, Messenger/metabolism Sequence Homology, Nucleic Acid Time Factors Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha/metabolism p38 Mitogen-Activated Protein Kinases
Chemicals
3' Untranslated Regions Luminescent Proteins RNA, Messenger Tumor Necrosis Factor-alpha Green Fluorescent Proteins Dactinomycin Granulocyte-Macrophage Colony-Stimulating Factor Phosphatidylinositol 3-Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Stoecklin Georg
Institute of Medical Microbiology, University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
Lu Min
Rattenbacher Bernd
Moroni Christoph
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.10.3506-3515.2003
Published
2003-05-00
Pages
3506-15
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC164766
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.23.10.3506-3515.2003 PMC Full Text View journal details
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