AU-rich element

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. 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. Shaw postulated that the conserved GM-CSF sequences must have a function as they were very similar to the conserved 3' UTR sequences that he had previously observed in mouse IFN-alpha genes.

A comparison of the mouse and human cDNAs encoding TNF (aka cachectin) in 1986 revealed that the TNF genes also shared an unusual conserved TTATTTAT sequence in their 3'UTRs, leading to speculation of a regulatory function that might be acting either at the DNA transcription level or at the mRNA level. After the discovery and publication by Shaw that AREs actually function at the mRNA level, ribonucleotide sequences with frequent adenine and uridine bases in 3' UTR of an mRNA were eventually classified (see description below). AREs often target the mRNA for rapid degradation. However, 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. 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. In 2025 it was reported that a synthetic ARE, with a certain configuration of AUUUA repeats that enhance HuR binding, can increase protein expression up to 5-fold. This finding may be useful for many mRNA-based therapeutics. Collectively, all of these observations suggest that it is the changing dynamic conditions within a cell that dictates how the ARE of an mRNA will function.

All of these data observations strongly suggest that AREs play a critical role in the regulation of gene expression during cell growth and differentiation, as well as the immune response. 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.

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.

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. Other ARE binding proteins (AUF1, TTP, BRF1, TIA-1, TIAR, and KSRP) destabilize the mRNA, miRNAs may also bind to some of them. 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. HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.

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