Nucleic Acids Research, 2001, Vol. 29, No. 4 863-871
© 2001 Oxford University Press
Polymorphism in the 3'-untranslated region of TNF
mRNA impairs binding of the post-transcriptional regulatory protein HuR to TNF mRNA
McGill University Health Center, McGill University, Department of Experimental Medicine, Montreal, Quebec H3G 1A4, Canada and 1Memorial Sloan-Kettering Cancer Center, Program in Molecular Pharmacology and Therapeutics, New York, NY 10021, USA
Tumor necrosis factor 
(TNF) acts as a beneficial mediator in the process of host defence. In recent years major interest has focused on the AU-rich elements (AREs) present in the 3'-untranslated region (3'-UTR) of TNF mRNA as this region plays a pivotal role in post-transcriptional control of TNF production. Certain stimuli, such as lipopolysaccharides, a component of the Gram-negative bacterial cell wall, have the ability to relinquish the translational suppression of TNF mRNA imposed by these AREs in macrophages, thereby enabling the efficient production of the TNF. In this study we show that the polymorphism (GAU trinucleotide insertional mutation) present in the regulatory 3'-UTR of TNF mRNA of NZW mice results in the hindered binding of RNA-binding proteins, thereby leading to a significantly reduced production of TNF protein. We also show that the binding of macrophage proteins to the main ARE is also decreased by another trinucleotide (CAU) insertion in the TNF 3'-UTR. One of the proteins affected by the GAU trinucleotide insertional mutation was identified as HuR, a nucleo-cytoplasmic shuttling protein previously shown to play a prominent role in the stability and translatability of mRNA containing AREs. Since binding of this protein most likely modulates the stability, translational efficiency and transport of TNF mRNA, these results suggest that mutations in the ARE of TNF mRNA decrease the production of TNF protein in macrophages by hindering the binding of HuR to the ARE.
* To whom correspondence should be addressed at: McGill University, Montreal General Hospital Research Institute, 1650 Cedar Avenue LH 11-218, Montreal, Quebec H3G 1A4, Canada. Tel: +1 514 937 6011; Fax: +1 514 934 8260; Email: danuta.radzioch{at}muhc.mcgill.ca
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