Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 23, Pages 22406-22417Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M500618200
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Funding
- NCI NIH HHS [R01 CA 102428, R01 CA102428] Funding Source: Medline
- NCRR NIH HHS [P41 RR008119, P41 RR 08119] Funding Source: Medline
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In mammals, rapid mRNA turnover directed by AU-rich elements (AREs) is mediated by selective association of cellular ARE-binding proteins. These trans-acting factors display overlapping RNA substrate specificities and may act to either stabilize or destabilize targeted transcripts; however, the mechanistic features of AREs that promote preferential binding of one trans-factor over another are not well understood. Here, we describe a hairpin-like structure adopted by the ARE from tumor necrosis factor alpha (TNF alpha) mRNA that modulates its affinity for selected ARE- binding proteins. In particular, association of the mRNA-destabilizing factor p37(AUF1) was strongly inhibited by adoption of the higher order ARE structure, whereas binding of the inducible heat shock protein Hsp70 was less severely compromised. By contrast, association of the mRNA-stabilizing protein HuR was only minimally affected by changes in ARE folding. Consistent with the inverse relationship between p37AUF1 binding affinity and the stability of ARE folding, mutations that stabilized the ARE hairpin also inhibited its ability to direct rapid mRNA turnover in transfected cells. Finally, phylogenetic analyses and structural modeling indicate that alpha(TNF alpha) mRNA sequences flanking the ARE are highly conserved and may stabilize the hairpin fold in vivo. Taken together, these data suggest that local higher order structures involving AREs may function as potent regulators of mRNA turnover in mammalian cells by modulating trans- factor binding selectivity.
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