Nucleic Acids Research, 1995, Vol. 23, No. 9 1461-1467
© 1995
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Defining a novel cis element in the 3'-untranslated region of mammalian ribonucleotide reductase component R2 mRNA: role in transforming growth factor-ß1 induced mRNA stabilization
Manitoba Institute of Cell Biology and Department of Biochemistry and Molecular Biology, University of Manitoba 100 Olivia Street, Winnipeg, Manitoba R3E 0V9, Canada
* To whom correspondence should be addressed
Received February 28, 1995. Accepted March 16, 1995.
Ribonucleotide reductase R2 gene expression is elevated In BALB/c 3T3 flbroblasts treated with transforming growth factor ß1 We investigated the possibility that the 3'-UTR of ribonucleotide reductase R2 mRNA contains regulatory Information for TGF-ß1 Induced message stability. Using end-labeled RNA fragments In gel shift assays and UV cross-linking analyses, we detected in the 3'-UTR a novel 9 nucleo-tide (nt) cls element, 5' -GAGUUUGAG-3' site, which Interacted specifically with a cytosolic protease sensitive factor to form a 75 kDa complex. The els element protein binding activity was induclble and markedly up-regulated cross-link 4 h after TGF-ß1 treatment of mouse BALB/c 3T3 cells. Other 3'-UTRs [IRE, GM-CSF, c-myc and homopolymer (U)] were poor competitors to the cls element with regard to forming the TGF-ß1 dependent RNA-proteln complex. However, the cls element effectively competed out the formation of the R2 3'-UTR protein complex. Cytosolic extracts from a variety of mammalian cell lines (monkey Cos7, several mouse fibrosarcomas and human HeLa S3) demonstrated similar TGF-ß1 dependent RNA-protein band shifts as cell extract from BALB/c 3T3 mouse fibro-blasts. Binding was completely prevented by several different mutations within the cls element, and by substitution mutagenesls, we were able to predict the consensus sequences, 5'-GAGUUUNNN-3' and 5'-NNNUUUGAG-3' for optimal protein binding. These results support a model in which the 9 nt region functions In cls to destabilize R2 mRNA in cells; and upon activation, a TGF-ß1 responsive protein is induced and interacts with the 9 nt cls element in a mechanism that leads to stabilization of the mRNA. This appears to be the first example of a mRNA binding site that is Involved In TGF-ß1-mediated effects.
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