Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the

3' untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

(UTR) of many messenger RNAs (

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

s) that code for proto-

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s, nuclear

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s, and

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...

s. AREs are one of the most common determinants of RNA stability in mammalian cells. AREs are defined as a region with frequent

adenine Adenine () (symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivativ ...

and

uridine Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nucl ...

bases in a

. They usually target the mRNA for rapid degradation. ARE-directed mRNA degradation is influenced by many exogenous factors, including phorbol esters, calcium

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as ...

s, cytokines, and transcription inhibitors. These observations suggest that AREs play a critical role in the regulation of gene transcription during cell growth and differentiation, and the

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

. AREs have been divided into three classes with different sequences. The best characterised adenylate uridylate (AU)-rich Elements have a core sequence of AUUUA within U-rich sequences (for example WWWU(AUUUA)UUUW where W is A or U). This lies within a 50–150 base sequence, repeats of the core AUUUA element are often required for function. A number of different

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s (e.g. HuA, HuB, HuC, HuD, HuR) bind to these elements and stabilise the mRNA while others (AUF1, TTP, BRF1, TIA-1, TIAR, and KSRP) destabilise the mRNA,

miRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...

s may also bind to some of them. HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.

AREsite AREsite is a database of AU-rich elements (ARE) in vertebrate mRNA 3'-untranslated regions ( UTRs). AU-rich elements are involved in the control of gene expression. They are the most common determinant of RNA stability in mammalian cells. The most ...

—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.

Classifications

*Class I ARE elements, like the

c-fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jin ...

gene, have dispersed AUUUA motifs within or near U-rich regions. *Class II elements, like the GM-CSF gene, have overlapping AUUUA motifs within or near U-rich regions. *Class III elements, like the

c-jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only la ...

gene, are a much less well-defined class—they have a U-rich region but no AUUUA repeats. No real ARE consensus sequence has been determined yet, and these categories are based neither on the same biological functions, nor on the homologous proteins.

Mechanism of ARE-mediated decay

AREs are recognized by RNA binding proteins such as tristetraprolin (TTP), AUF1, and Hu Antigen R ( HuR). Although the exact mechanism is not very well understood, recent publications have attempted to propose the action of some of these proteins. AUF1, also known as hnRNP D, binds AREs through

RNA recognition motif RNA recognition motif, RNP-1 is a putative RNA-binding domain of about 90 amino acids that are known to bind single-stranded RNAs. It was found in many eukaryotic proteins. The largest group of single strand RNA-binding protein is the eukaryot ...

s (RRMs). AUF1 is also known to interact with the translation initiation factor eIF4G and with poly(A)-binding protein, indicating that AUF1 senses the translational status of mRNA and decays accordingly through the excision of the poly(A) tail. Animation455

TTP's expression is rapidly induced by insulin. Immunoprecipitation experiments have shown that TTP co-precipitates with an

exosome Exosome may refer to: * Exosome complex The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein intracellular complex capable of degrading various types of RNA (ribonucleic acid) molecules. Exosome complexes ...

, suggesting that it helps recruit exosomes to the

containing AREs. Alternatively, HuR proteins have a stabilizing effect—their binding to AREs increases the half-life of

s. Similar to other RNA-binding proteins, this class of proteins contain three RRMs, two of which are specific to ARE elements. A likely mechanism for HuR action relies on the idea that these proteins compete with other proteins that normally have a destabilizing effect on

s. HuRs are involved in genotoxic response—they accumulate in the cytoplasm in response to UV exposure and stabilize

s that encode proteins involved in DNA repair.

Disease

Problems with mRNA stability have been identified in viral genomes,

cancer cell Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these ...

s, and various diseases. Research shows that many of these problems arise because of faulty ARE function. Some of these problems have been listed below: * The

gene produces a transcription factor that is activated in several cancers, and it lacks the ARE elements. *

c-myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...

gene, also responsible for producing transcription factors found in several cancers, has also been reported to lack the ARE elements. * The

Cox-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

gene catalyses the production of

prostaglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deri ...

—it overexpresses in several cancers, and is stabilized by the binding of CUGBP2 RNA-binding protein to ARE

References

External links

Review of original publication discovering AU-rich elementsPillars link to original 1986 Cell publication discovering AU-rich elementsmRNA Translational blockade by AU-rich elementsARED: AU-rich element databaseTransterm page for AU-Rich ElementAREsite: An online resource for the analysis of AREs
{{DEFAULTSORT:Au-Rich Element RNA Gene expression Cis-regulatory RNA elements