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PMID: 12198173 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Functional cloning of BRF1, a regulator of ARE-dependent mRNA turnover.

The EMBO journal ·Vol. 21 ·No. 17 ·2002-09-02 ·Pages 4709-18

Stoecklin G, Colombi M, Raineri I, Leuenberger S, Mallaun M, Schmidlin M, Gross B, Lu M, Kitamura T, Moroni C

Abstract

To identify regulators of AU-rich element (ARE)-dependent mRNA turnover we have followed a genetic approach using a mutagenized cell line (slowC) that fails to degrade cytokine mRNA. Accordingly, a GFP reporter construct whose mRNA is under control of the ARE from interleukin-3 gives an increased fluorescence signal in slowC. Here we describe rescue of slowC by a retroviral cDNA library. Flow cytometry allowed us to isolate revertants with reconstituted rapid mRNA decay. The cDNA was identified as butyrate response factor-1 (BRF1), encoding a zinc finger protein homologous to tristetraprolin. Mutant slowC carries frame-shift mutations in both BRF1 alleles, whereas slowB with intermediate decay kinetics is heterozygous. By use of small interfering (si)RNA, independent evidence for an active role of BRF1 in mRNA degradation was obtained. In transiently transfected NIH 3T3 cells, BRF1 accelerated mRNA decay and antagonized the stabilizing effect of PI3-kinase, while mutation of the zinc fingers abolished both function and ARE-binding activity. This approach, which identified BRF1 as an essential regulator of ARE-dependent mRNA decay, should also be applicable to other cis-elements of mRNA turnover.

MeSH Terms
3' Untranslated Regions/genetics 3T3 Cells Animals Butyrate Response Factor 1 Cloning, Molecular Codon, Nonsense Cytokines/genetics DNA, Complementary/genetics DNA-Binding Proteins Fibrosarcoma/chemistry,pathology Frameshift Mutation Genes, Reporter Genetic Complementation Test Humans Immediate-Early Proteins/analysis,chemistry Mice Neoplasm Proteins/genetics,isolation & purification Phosphoinositide-3 Kinase Inhibitors RNA Stability RNA, Messenger/metabolism RNA, Small Interfering RNA, Untranslated/metabolism Saccharomyces cerevisiae Proteins Structure-Activity Relationship Subcellular Fractions/chemistry TATA-Binding Protein Associated Factors Transcription Factor TFIIIB Transcription Factors/genetics,isolation & purification,physiology Transfection Tristetraprolin Tumor Cells, Cultured/chemistry Zinc Fingers/genetics
Chemicals
3' Untranslated Regions BRF1 protein, S cerevisiae BRF1 protein, human Butyrate Response Factor 1 Codon, Nonsense Cytokines DNA, Complementary DNA-Binding Proteins Immediate-Early Proteins Neoplasm Proteins Phosphoinositide-3 Kinase Inhibitors RNA, Messenger RNA, Small Interfering RNA, Untranslated Saccharomyces cerevisiae Proteins TATA-Binding Protein Associated Factors Transcription Factor TFIIIB Transcription Factors Tristetraprolin ZFP36 protein, human Zfp36 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Stoecklin Georg
Institute of Medical Microbiology, University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Colombi Marco
Raineri Ines
Leuenberger Sabrina
Mallaun Michel
Schmidlin Martin
Gross Brigitte
Lu Min
Kitamura Toshio
Moroni Christoph
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf444
Published
2002-09-02
Pages
4709-18
Language
English
Region
England
NLM ID
8208664
PMCID
PMC126184
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdf444 PMC Full Text View journal details
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