Cytokines & Cells Online Pathfinder Encyclopaedia
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[AU-rich element; also abbr. AURE; adenylate uridylate-rich elements] There is a large range of mRNA half-lives in cells, and there are both general and specific degradation signals in mRNAs. While the primary sequence of any specific mRNA is constant, the half-lives of many mRNAs change dependent on cell cycle and environmental influences; many mRNAs are more stable when cells are proliferating, suggesting that there must be other important signals influencing their half-lives.
The AU-rich element is a pentanucleotide sequence element, referred to also as mRNA decay element, which consists of one or more AUUUA tandem repetitions embedded in a uracil-rich region found in the 3' untranslated regions of a variety of mRNAs.
The presence of these cis-acting elements has been shown to shorten mRNA half-lifes in mammalian cells. If such sequence elements are introduced into mRNAs that do not contain them, e. g., stable beta-globin mRNA, this leads to a rapid decay of these engineered mRNAs in vivo. Although the mechanism by which the AU-rich element promotes mRNA decay is not known release of intracellular calcium stores inhibits the rapid turnover of AU-rich interleukin mRNAs probably by altering trans-acting decay factors.
AU-rich sequences are the most common RNA-destabilizing elements known in mammalian cells. In addition, there exist other destabilizing elements such as stem-loop destabilizing elements (SLDE) found in the 3' untranslated regions of mRNAs encoding GM-CSF, IL2, and IL6, that may interfere with mRNA stability in a manner that is independent of the ARE.
The control of mRNA stability is becoming recognized as a crucial point of gene expression regulation and thus the ability to control differential decay of mRNA is not just a "clean-up" role. It is useful also for work in engineering cells.
The modulation of mRNA half-life by selective degradation of mRNA appears to be one of the mechanisms allowing transient expression of genes (see also: gene expression; see also: Early response gene). On the other hand, selective transcript stabilization, probably mediated by cytoplasmic inhibitors of selective ribonucleases, also occurs and may be a common ingredient of most inductive stimuli.
An AU-rich sequence motif has been found in many transcripts encoding growth factors and cytokines, growth factor-like substances, Oncogene, and other proteins with growth-regulating activities that are subjected to fast expression changes in response to various stimuli. This motif has been observed, for example, in the genes encoding IL1, IL3 (see also: FL5.12 cell line), IL8, GM-CSF, IFN-gamma, PF4 (platelet factor-4), TNF-alpha, EGF, and sis, jun, ets, raf, myc, fos, BCL2. Dominquez et al (1998) have described a procedure suitable for cloning labile mRNAs that contain AU sequence motifs.
Mutant mice expressing a mutant form of TNF from which the AU-rich elements were removed have been shown to develop chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggesting that defective function of ARE may be involved in the etiology also of analogous human diseases.
A number of AU-binding factors have been discovered recently, suggesting that specific regulation may occur through specific protein-mRNA interaction(s). The mechanisms by which these trans-acting proteins influence ARE-directed mRNA turnover are presently unclear but it is thought that these proteins may participate in the assembly of larger protein/mRNA complexes that then mediate mRNA degradation. Moreover, mRNA decay, through the participation of ARE-binding proteins appears to be linked intimately to other cellular processes.
AUBF (adenosine-uridine binding factor) is a cytosolic phosphoprotein that binds to, and stabilizes, four AUUUA tandem repetitions found in the 3' untranslated regions of certain mRNAs. AUF1 is a protein of 37 kDa that binds specifically to the 3' untranslated AU-rich regions of mRNAs encoding, among others, myc and GM-CSF, BCL2. This protein complexes with one of the heat shock proteins, hsc70 - hsp70, translation initiation factor eIF4G, and poly(A) binding protein. mRNA decay mediated through the AU-rich sequence is associated with displacement of eIF4G from AUF1, attachment of ubiquitin to AUF1, and degradation of AUF1 by proteasomes. mRNA decay is blocked if upon induction of hsp70, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1. AUF1 also binds to CDIR [cell death inhibiting RNA], which influences mRNA decay and has a profound effect on cell death by apoptosis. Lappucci et al (2002) have reported that AUF1 binds to the AU-rich element of the anti-apoptotic protein BCL2 and is involved in mRNA destabilization of this mRNA, thus affecting apoptosis.
AUH is an AU-specific RNA-binding protein that has been shown to possess an intrinsic enoyl-CoA hydratase activity, which may function to link mRNA decay to metabolic processes.
The Drosophila melanogaster locus ELAV [embryonic lethal abnormal visual] encodes a nuclear RNA-binding protein expressed exclusively in neurons. The protein is essential for normal neuronal differentiation and maintenance of neurons. Proteins displaying structural homology to the ELAV protein have been found in a wide variety of species and constitute a highly conserved family of RNA-binding proteins in vertebrates. In humans, there are four members; HuR (called also HuA) is expressed in all proliferating cells, whereas Hel-N1 (human elav-like neuronal protein 1; called also HuB), HuC and HuD are expressed in terminally differentiated neurons. These proteins contain RNA-binding domains and appear to increase the in vivo stability of mRNAs containing ARE sequence elements.
Tristetraprolin (TTP) (also known as Zfp36 or nup475) is a cytosolic Cys-Cys-Cys-His zinc finger protein that binds to AU-rich elements in TNF-alpha mRNA and inhibits TNF-alpha production from macrophages by destabilizing its mRNA. TTP appears to be a component of a negative feedback loop interfering with TNF-alpha production since its synthesis is induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself.
Rajagopalan et al (1995) have used the expression of GM-CSF genes carrying a mutated AUUUA instability element as a strategy to effect enhanced production of a biologically active cytokine by normal cells after in vivo gene transfer.
Houzet et al (2001) have studied the importance of ARE in the control of GM-CSF gene expression in vivo by generating transgenic mice bearing GM-CSF gene constructs lacking ARE. At day 14 of embryonic development (E14) ARE-deleted but not ARE-containing constructs are expressed. Overexpression of GM-CSF in E14 GM-CSF AU(-) embryos severely affects hematopoiesis and leads to abnormal proliferation of granulocytes and macrophages. Viable pups cannot be obtained from GM-CSF AU(-) embryos.
Bakheet et al (2001) have described the establishment of a data base collecting information about human mRNAs containing AU-rich elements.
LAST MODIFIED: March 2004
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