Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common determinants of RNA stability in mammalian cells and can also modulate mRNA translation.[1][2] The function of AREs was originally discovered by Shaw and Kamen in 1985, when Gray Shaw transferred the ARE from the 3' UTR of the human GM-CSF gene into the 3' UTR of a rabbit beta-globin gene.[3][4][5]
A comparison of the mouse and human cDNAs encoding TNF (aka cachectin) in 1986 revealed that they shared an unusual TTATTTAT sequence in their 3'UTRs suggesting a regulatory function that might be acting on either DNA or RNA sequences.[6] After the discovery and publication by Shaw that AREs are functioning at the mRNA level, ribonucleotide sequences with frequent adenine and uridine bases in 3' UTR of an mRNA were classified (see description below). They usually target the mRNA for rapid degradation.[7][3] ARE-directed mRNA degradation is influenced by many exogenous factors, including phorbol esters, calcium ionophores, cytokines, and transcription inhibitors. In 1989, it was reported that AREs could sometimes function to block the translation of mRNAs.[2] Further research revealed that AREs could sometimes also function to increase translation of mRNAs by recruiting the microRNP-related proteins FXR1 and AGO2 during conditions of cell cycle arrest.[8] These observations suggest that the changing dynamic conditions within a cell dictates how the ARE of an mRNA will function.
All of these observations suggest that AREs play a critical role in the regulation of gene expression during cell growth and differentiation, as well as the immune response.[1][9] As evidence of its critical role, deletion of the AREs from the 3' UTR in either the TNF gene or GM-CSF gene in mice leads to over expression of each respective gene product, causing dramatic disease phenotypes.[10][11][12]
AREs have been divided into three classes with different sequences. The best characterized 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 single AUUUA shows very little mRNA destabilizing function, whereas AUUUAUUUAUUUA shows some mRNA destabilizing function when inserted into the 3'UTR of a rabbit beta-globin gene.[13]
A number of different proteins (e.g. HuA, HuB, HuC, HuD, HuR) bind to these elements and stabilise the mRNA. The sequence AUUUAUUUA is the minimal sequence required for HuR binding and multiple AUUUA sequences can be inserted at the beginning of the 3' UTR to maximize HuR binding.[14] Other ARE binding proteins (AUF1, TTP, BRF1, TIA-1, TIAR, and KSRP) destabilize the mRNA, miRNAs may also bind to some of them.[15] For example, the human microRNA, miR16, contains an UAAAUAUU sequence that is complementary to the ARE sequence and appears to be required for ARE-mRNA turnover.[16]HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.[17]
AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.[18]
Classifications
Class I ARE elements, like the c-fos 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 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.[7]
Mechanism of ARE-mediated decay
AREs are recognized by RNA binding proteins such as tristetraprolin (TTP), AUF1, and Hu Antigen R (HuR).[19] 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 motifs (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.[19]
The proposed mechanism for which ARE elements function & control sequencing.
TTP's (ZFP36's) expression is rapidly induced by insulin.[20] Immunoprecipitation experiments have shown that TTP co-precipitates with an exosome, suggesting that it helps recruit exosomes to the mRNA containing AREs.[21] Alternatively, HuR proteins have a stabilizing effect—their binding to AREs increases the half-life of mRNAs. Similar to other RNA-binding proteins, this class of proteins contain three RRMs, two of which are specific to ARE elements.[22] A likely mechanism for HuR action relies on the idea that these proteins compete with other proteins that normally have a destabilizing effect on mRNAs.[23]HuRs are involved in genotoxic response—they accumulate in the cytoplasm in response to UV exposure and stabilize mRNAs that encode proteins involved in DNA repair.
Disease
Problems with mRNA stability have been identified in viral genomes, cancer cells, and various diseases. Research shows that many of these problems arise because of faulty ARE function. Deficiency of the ZFP36 family show that ZFP36 ARE binding proteins are critical regulators of T cell homeostasis and autoimmunity.[24] Some of these problems have been listed below:[19]
The c-fos gene produces a transcription factor that is activated in several cancers, the ARE present in c-fos plays a role in its post-transcriptional regulation.
c-myc gene, also responsible for producing transcription factors found in several cancers, the ARE present in c-myc plays a role in its post-transcriptional regulation.
The Cox-2 gene catalyses the production of prostaglandins—it overexpresses in several cancers, and is stabilized by the binding of CUGBP2 RNA-binding protein to ARE
References
1 2 Chen, Chyi-Ying A.; Shyu, Ann-Bin (November 1995). "AU-rich elements: characterization and importance in mRNA degradation". Trends in Biochemical Sciences. 20 (11): 465–470. doi:10.1016/S0968-0004(00)89102-1. PMID8578590.
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