{{Short description|RNA sequences}} '''Adenylate-uridylate-rich elements''' ('''AU-rich elements'''; '''AREs''') are nucleotide sequences 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.<ref name="Chen 465–470">{{cite journal|last=Chen|first=Chyi-Ying A.|author2=Shyu, Ann-Bin|title=AU-rich elements: characterization and importance in mRNA degradation|journal=Trends in Biochemical Sciences|date=November 1995|volume=20|issue=11|pages=465–470|pmid=8578590|doi=10.1016/S0968-0004(00)89102-1}}</ref><ref name=":1" /> The function of AREs was originally discovered in 1985 by Gray Shaw while in Robert Kamen's research lab at Genetics Institute, 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.<ref name=":0" /><ref>{{Cite journal |last1=Beisang |first1=Daniel |last2=Bohjanen |first2=Paul R. |date=2012 |title=Perspectives on the ARE as it turns 25 years old |journal=Wiley Interdisciplinary Reviews. RNA |volume=3 |issue=5 |pages=719–731 |doi=10.1002/wrna.1125 |issn=1757-7012 |pmc=4126804 |pmid=22733578}}</ref><ref name="ReferenceA">{{Cite journal |last1=Turner |first1=Martin |last2=Katsikis |first2=Peter D. |date=2012-07-01 |title=A new mechanism of gene regulation mediated by noncoding RNA |journal=Journal of Immunology |volume=189 |issue=1 |pages=3–4 |doi=10.4049/jimmunol.1201339 |issn=1550-6606 |pmid=22723637}}</ref> The transfer of the GM-CSF ARE caused the otherwise stable beta-globin mRNA to rapidly decay. Shaw had previously postulated that the conserved GM-CSF sequences must have a function as they were very similar to the conserved 3' UTR sequences of ATTTA that he had previously observed in mouse and human IFN-alpha genes in 1983.<ref>{{Cite journal |last1=Shaw |first1=G. D. |last2=Boll |first2=W. |last3=Taira |first3=H. |last4=Mantei |first4=N. |last5=Lengyel |first5=P. |last6=Weissmann |first6=C. |date=1983-02-11 |title=Structure and expression of cloned murine IFN-alpha genes |journal=Nucleic Acids Research |volume=11 |issue=3 |pages=555–573 |doi=10.1093/nar/11.3.555 |issn=0305-1048 |pmc=325737 |pmid=6188104}}</ref>
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.<ref>{{Cite journal |last1=Caput |first1=D. |last2=Beutler |first2=B. |last3=Hartog |first3=K. |last4=Thayer |first4=R. |last5=Brown-Shimer |first5=S. |last6=Cerami |first6=A. |date=March 1986 |title=Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=83 |issue=6 |pages=1670–1674 |doi=10.1073/pnas.83.6.1670 |doi-access=free |issn=0027-8424 |pmc=323145 |pmid=2419912|bibcode=1986PNAS...83.1670C }}</ref> After the discovery and publication by Shaw that AREs don't function at the DNA level but rather in mRNA, ribonucleotide sequences with frequent adenine and uridine bases in 3' UTR of an mRNA were eventually classified (see description below). While AREs often target the mRNA for rapid degradation,<ref name="Barreau 7138–7150">{{cite journal |author1=C Barreau, L Paillard |author2=H B Osborne |name-list-style=amp |title=AU-rich elements and associated factors: are there unifying principles? |journal=Nucleic Acids Res |volume=33 |pages=7138–7150 |year=2006 |pmid=16391004 |doi=10.1093/nar/gki1012 |issue=22 |pmc=1325018}}</ref><ref name=":0">{{cite journal |vauthors=Shaw G, Kamen R |title=A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation |journal=Cell |volume=46 |issue=5 |pages=659–667 |date=August 1986 |pmid=3488815 |doi=10.1016/0092-8674(86)90341-7|s2cid=40332253 }}</ref> ARE-directed mRNA degradation can be influenced by many exogenous factors that modulate a cell's function, including phorbol esters, calcium ionophores, cytokines, and transcription inhibitors. In 1989, Kruys and Shaw reported that AREs could also function to block the translation of mRNAs, using Xenopus oocytes as the translational assay system.<ref name=":1">{{Cite journal |last1=Kruys |first1=V. |last2=Marinx |first2=O. |last3=Shaw |first3=G. |last4=Deschamps |first4=J. |last5=Huez |first5=G. |date=1989-08-25 |title=Translational blockade imposed by cytokine-derived UA-rich sequences |journal=Science |volume=245 |issue=4920 |pages=852–855 |doi=10.1126/science.2672333 |issn=0036-8075 |pmid=2672333|bibcode=1989Sci...245..852K |hdl=2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/56761 |hdl-access=free }}</ref> This blockade could be explained by the binding of the ELAVL2 isoform that is found in oocytes to AREs.<ref>{{Cite journal |last=Chalupnikova |first=Katerina |last2=Solc |first2=Petr |last3=Sulimenko |first3=Vadym |last4=Sedlacek |first4=Radislav |last5=Svoboda |first5=Petr |date=2014 |title=An oocyte-specific ELAVL2 isoform is a translational repressor ablated from meiotically competent antral oocytes |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC4013169/ |journal=Cell Cycle (Georgetown, Tex.) |volume=13 |issue=7 |pages=1187–1200 |doi=10.4161/cc.28107 |issn=1551-4005 |pmc=4013169 |pmid=24553115}}</ref> 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.<ref>{{Cite journal |last1=Vasudevan |first1=Shobha |last2=Steitz |first2=Joan A. |date=2007-03-23 |title=AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2 |journal=Cell |volume=128 |issue=6 |pages=1105–1118 |doi=10.1016/j.cell.2007.01.038 |issn=0092-8674 |pmc=3430382 |pmid=17382880}}</ref> 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.<ref name="Molecular Therapy 2025">{{Cite journal |last1=Ma |first1=Xinghuan |last2=Liu |first2=Sujia |last3=Fan |first3=Bangda |last4=Jin |first4=Danni |last5=Miao |first5=Lei |last6=Liu |first6=Lin |last7=Du |first7=Shubo |last8=Lin |first8=Jiaqi |date=2025-06-10 |title=Enhancing mRNA translation efficiency by introducing sequence optimized AU-rich elements in 3' UTR via HuR anchorage |journal=Molecular Therapy. Nucleic Acids |volume=36 |issue=2 |article-number=102485 |doi=10.1016/j.omtn.2025.102485 |issn=2162-2531 |pmc=11930071 |pmid=40125272}}</ref><ref>{{Cite journal |last1=Froechlich |first1=Guendalina |last2=Sasso |first2=Emanuele |date=2025-06-10 |title=We ARE boosting translation: AU-rich elements for enhanced therapeutic mRNA translation |journal=Molecular Therapy. Nucleic Acids |volume=36 |issue=2 |article-number=102531 |doi=10.1016/j.omtn.2025.102531 |issn=2162-2531 |pmc=12018973 |pmid=40276699}}</ref> Collectively, all of these observations suggest that receptor signaling and the local changing dynamic conditions within a cell (including starvation and stress) dictates how the ARE of an mRNA will function.<ref name=":2">{{Cite journal |last1=Newman |first1=R |last2=McHugh |first2=J |last3=Turner |first3=M |date=2016-01-01 |title=RNA binding proteins as regulators of immune cell biology |journal=Clinical and Experimental Immunology |volume=183 |issue=1 |pages=37–49 |doi=10.1111/cei.12684 |pmid=26201441 |issn=0009-9104|pmc=4687516 }}</ref>
Each 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.<ref name="Chen 465–470" /><ref name="ReferenceA"/><ref name=":2" /> 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. In short, the AU-rich element illustrates how after genes are transcribed into mRNA, there is another level of control that can determine how much protein will be translated from an mRNA (posttransciptional gene regulation).<ref>{{Cite journal |last1=Kontoyiannis |first1=D. |last2=Pasparakis |first2=M. |last3=Pizarro |first3=T. T. |last4=Cominelli |first4=F. |last5=Kollias |first5=G. |date=March 1999 |title=Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies |journal=Immunity |volume=10 |issue=3 |pages=387–398 |doi=10.1016/s1074-7613(00)80038-2 |issn=1074-7613 |pmid=10204494|doi-access=free }}</ref><ref>{{Cite journal |last1=Houzet |first1=L. |last2=Morello |first2=D. |last3=Defrance |first3=P. |last4=Mercier |first4=P. |last5=Huez |first5=G. |last6=Kruys |first6=V. |date=2001-09-01 |title=Regulated control by granulocyte-macrophage colony-stimulating factor AU-rich element during mouse embryogenesis |journal=Blood |volume=98 |issue=5 |pages=1281–1288 |doi=10.1182/blood.v98.5.1281 |issn=0006-4971 |pmid=11520772}}</ref><ref>{{Cite journal |last1=Arao |first1=Yukitomo |last2=Stumpo |first2=Deborah J. |last3=Hoenerhoff |first3=Mark J. |last4=Tighe |first4=Robert M. |last5=Yu |first5=Yen-Rei |last6=Sutton |first6=Deloris |last7=Kashyap |first7=Amogh |last8=Beerman |first8=Isabel |last9=Blackshear |first9=Perry J. |date=August 2023 |title=Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA |journal=FASEB Journal|volume=37 |issue=8 |pages=e23100 |doi=10.1096/fj.202300757R |doi-access=free |issn=1530-6860 |pmid=37462673|pmc=11078221 }}</ref>
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.<ref>{{Cite journal |last1=Akashi |first1=M. |last2=Shaw |first2=G. |last3=Hachiya |first3=M. |last4=Elstner |first4=E. |last5=Suzuki |first5=G. |last6=Koeffler |first6=P. |date=1994-06-01 |title=Number and location of AUUUA motifs: role in regulating transiently expressed RNAs |journal=Blood |volume=83 |issue=11 |pages=3182–3187 |doi=10.1182/blood.V83.11.3182.3182 |issn=0006-4971 |pmid=8193353}}</ref>
A number of different proteins (e.g. HuA, HuB, HuC, HuD, HuR) bind to these elements and stabilize 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.<ref name="Molecular Therapy 2025"/><ref>{{Cite journal |last=Froechlich |first=Guendalina |last2=Sasso |first2=Emanuele |date=2025-06-10 |title=We ARE boosting translation: AU-rich elements for enhanced therapeutic mRNA translation |journal=Molecular Therapy. Nucleic Acids |volume=36 |issue=2 |article-number=102531 |doi=10.1016/j.omtn.2025.102531 |issn=2162-2531 |pmc=12018973 |pmid=40276699}}</ref> HuR contains three RNA recognition motifs (RRMs): Tandem RRM1 and 2, followed by a flexible linker and a C-terminal RRM3. The co-crystal structure of RRM3 provides structural and mechanistic insights into how RRM3 in HuR binds to various AU-rich sequences.<ref>{{Cite journal |last=Ripin |first=Nina |last2=Boudet |first2=Julien |last3=Duszczyk |first3=Malgorzata M. |last4=Hinniger |first4=Alexandra |last5=Faller |first5=Michael |last6=Krepl |first6=Miroslav |last7=Gadi |first7=Abhilash |last8=Schneider |first8=Robert J. |last9=Šponer |first9=Jiří |last10=Meisner-Kober |first10=Nicole C. |last11=Allain |first11=Frédéric H.-T. |date=2019-02-19 |title=Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=116 |issue=8 |pages=2935–2944 |doi=10.1073/pnas.1808696116 |issn=1091-6490 |pmc=6386705 |pmid=30718402}}</ref> The RNA binding protein RMB47 has been shown to bind to AREs in IL-10 mRNA and Ectodermal neural cortex 1 (ENC1) mRNA and stabilize those mRNAs.<ref>{{Cite journal |last=Wei |first=Yinxiang |last2=Zhang |first2=Fanghui |last3=Zhang |first3=Yu |last4=Wang |first4=Xiaoqian |last5=Xing |first5=Chen |last6=Guo |first6=Jing |last7=Zhang |first7=Hui |last8=Suo |first8=Zhimin |last9=Li |first9=Yan |last10=Wang |first10=Jianli |last11=Wang |first11=Renxi |last12=Cai |first12=Zhijian |date=June 2019 |title=Post-transcriptional regulator Rbm47 elevates IL-10 production and promotes the immunosuppression of B cells |journal=Cellular & Molecular Immunology |volume=16 |issue=6 |pages=580–589 |doi=10.1038/s41423-018-0041-z |issn=2042-0226 |pmc=6804925 |pmid=29844590}}</ref><ref>{{Cite journal |last=Li |first=Yangxue |last2=Shi |first2=Henghe |last3=Lu |first3=Yang |last4=Wu |first4=Junduo |date=2026-04-08 |title=RNA-binding protein RBM47 enhances ENC1 stability through AU-rich elements to induce oxidative stress in macrophages in atherosclerosis progression |journal=Biochemical Pharmacology |volume=250 |issue=Pt 1 |article-number=117953 |doi=10.1016/j.bcp.2026.117953 |issn=1873-2968 |pmid=41962778}}</ref> Other ARE binding proteins (AUF1, TTP, BRF1, TIA-1, TIAR, and KSRP) destabilize the mRNA, miRNAs may also bind to some of them.<ref>{{cite journal |author1=Federico Bolognani |author2=Nora Perrone-Bizzozero |name-list-style=amp |title=RNA-protein interactions and control of mRNA stability in neurons |journal=J Neurosci Res |volume=86 |pages=481–489 |year=2008 |pmid=17853436 |doi=10.1002/jnr.21473 |issue= 3|s2cid=27076039 }}</ref> 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.<ref>{{Cite journal |last1=Q |first1=Jing |last2=S |first2=Huang |last3=S |first3=Guth |last4=T |first4=Zarubin |last5=A |first5=Motoyama |last6=J |first6=Chen |last7=F |first7=Di Padova |last8=Sc |first8=Lin |last9=H |first9=Gram |last10=J |first10=Han |date=2005-03-11 |title=Involvement of microRNA in AU-rich element-mediated mRNA instability |journal=Cell |language=en |volume=120 |issue=5 |pages=623–634 |doi=10.1016/j.cell.2004.12.038 |issn=0092-8674 |pmid=15766526|doi-access=free }}</ref> HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.<ref>{{cite journal |author1=Nora Perrone-Bizzozero |author2=Federico Bolognani |name-list-style=amp |title=Role of HuD and other RNA-binding proteins in neural development and plasticity |journal=J Neurosci Res |volume=68 |pages=121–126 |year=2002 |pmid=11948657 |doi=10.1002/jnr.10175 |issue=2|title-link=HuD |doi-access=free }}</ref> The RNA binding protein DDX21 has been reported to bind to AREs and confer mTOR-mediated translation control of cytokines during T cell activation.<ref>{{Cite journal |last=Jurgens |first=Anouk P. |last2=Zwijnen |first2=Josephine |last3=Bradarić |first3=Antonia |last4=van Alphen |first4=Floris P. J. |last5=Bresser |first5=Kaspar |last6=Rooijers |first6=Koos |last7=Hoogendijk |first7=Arie J. |last8=Popović |first8=Branka |last9=Wolkers |first9=Monika C. |date=2025-12-04 |title=mTOR signaling during T cell activation promotes cytokine production in T cells through 3' UTR-mediated translation control |journal=Molecular Cell |volume=85 |issue=23 |pages=4452–4462.e5 |doi=10.1016/j.molcel.2025.11.005 |issn=1097-4164 |pmid=41349520}}</ref>
AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.<ref>{{cite journal |vauthors=Gruber AR, Fallmann J, Kratochvill F, Kovarik P, Hofacker IL |title=AREsite: a database for the comprehensive investigation of AU-rich elements |journal=Nucleic Acids Res |volume=39 |pages=D66–9 |year=2011 |pmid=21071424 |doi=10.1093/nar/gkq990 |issue=Database issue |pmc=3013810}}</ref>
==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.<ref name="Barreau 7138–7150"/>
==Mechanism of ARE-mediated decay== AREs are recognized by RNA binding proteins such as tristetraprolin (TTP),<ref>{{Cite journal |last=Carballo |first=E. |last2=Lai |first2=W. S. |last3=Blackshear |first3=P. J. |date=1998-08-14 |title=Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin |journal=Science |volume=281 |issue=5379 |pages=1001–1005 |doi=10.1126/science.281.5379.1001 |issn=0036-8075 |pmid=9703499}}</ref> AUF1, and Hu Antigen R (HuR).<ref name="Ref1">{{cite book|last1=Elliott|first1=David|last2=Ladomery|first2=Michael|title=Stability and Degradation of mRNA|date=2011|publisher=Oxford UP|location=Oxford|page=312}}</ref> RNA-binding proteins that bind AREs have been termed ARE-BPs and as of 2019, about 20 ARE-BPs have been identified.<ref name=":3">{{Cite journal |last1=Otsuka |first1=Hiroshi |last2=Fukao |first2=Akira |last3=Funakami |first3=Yoshinori |last4=Duncan |first4=Kent E. |last5=Fujiwara |first5=Toshinobu |date=2019 |title=Emerging Evidence of Translational Control by AU-Rich Element-Binding Proteins |journal=Frontiers in Genetics |volume=10 |article-number=332 |doi=10.3389/fgene.2019.00332 |doi-access=free |issn=1664-8021 |pmc=6507484 |pmid=31118942}}</ref> Although the exact mechanism is not very well understood, recent publications have attempted to propose the action of some of these ARE-BPs. One characteristic of many ARE-BPs is that they can shuttle between the nucleus and cytoplasm and exert different functions to control gene expression based on their subcellular location.<ref name=":3" /> 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.<ref name="Ref1" /> thumb|x180px|alt=Proposed ARE Element Mechanism.|The proposed mechanism for which ARE elements function & control sequencing. TTP's (ZFP36's) expression is rapidly induced by insulin.<ref>{{cite journal|last1=Cao|first1=H|last2=JF Jr|first2=Urban|last3=RA|first3=Anderson|title=Insulin Increases Tristetraprolin and Decreases VEGF Gene Expression in Mouse 3T3-L1 Adipocytes|journal=Obesity|date=Apr 2008|volume=16|issue=6|pages=1208–1218|doi=10.1038/oby.2008.65|pmid=18388887|s2cid=19149343|doi-access=free}}</ref> Immunoprecipitation experiments have shown that TTP co-precipitates with an exosome, suggesting that it helps recruit exosomes to the mRNA containing AREs.<ref>{{cite journal|last1=Tiedje|first1=Christopher|last2=Kotlyarov|first2=Alexey|last3=Gaestel|first3=Matthias|title=Molecular Mechanisms of Phosphorylation-regulated TTP (tristetraprolin) Action and Screening for Further TTP-interacting Proteins|journal=Biochemical Society Transactions|date=2010|volume=38|issue=6|pages=1632–1637|url=http://www.mh-hannover.de/fileadmin/institute/physiologische_chemie/2010_Biochem_Soc_Transact_38-1632_Tietje_et_al.pdf|doi=10.1042/bst0381632|pmid=21118139}}</ref> TTP appears to promote the processive deadenylation activity of CCR4–NOT on mRNAs containing AREs, with phosphorylation-dependent interactions with cytoplasmic poly(A)-binding protein (PABPC1) potentially enhancing deadenylation and promoting regulated mRNA decay.<ref>{{Cite journal |last1=Pekovic |first1=Filip |last2=Lai |first2=Wi S. |last3=Corbo |first3=Joshua |last4=Hicks |first4=Stephanie N. |last5=Luke |first5=Keiko |last6=Blackshear |first6=Perry J. |last7=Valkov |first7=Eugene |date=2025-08-13 |title=Multivalent interactions with CCR4-NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin |journal=Nature Communications |volume=16 |issue=1 |page=7528 |doi=10.1038/s41467-025-62741-7 |issn=2041-1723 |pmc=12350847 |pmid=40804313 |bibcode=2025NatCo..16.7528P }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> TTP can also repress mRNA translation after binding to AREs by using 4EHP-GYF2 as a cofactor.<ref>{{Cite journal |last=Fu |first=Rui |last2=Olsen |first2=Myanna T. |last3=Webb |first3=Kristofor |last4=Bennett |first4=Eric J. |last5=Lykke-Andersen |first5=Jens |date=March 2016 |title=Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements |url=https://pubmed.ncbi.nlm.nih.gov/26763119 |journal=RNA (New York, N.Y.) |volume=22 |issue=3 |pages=373–382 |doi=10.1261/rna.054833.115 |issn=1469-9001 |pmc=4748815 |pmid=26763119}}</ref> 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.<ref>{{cite journal|last1=Dai|first1=Weijun|last2=Zhang|first2=Gen|last3=Makeyev|first3=Eugene V.|title=RNA-binding Protein HuR Autoregulates Its Expression by Promoting Alternative Polyadenylation Site Usage|journal=Nucleic Acids Research|date=24 Sep 2011|volume=40|issue=2|pages=787–800|doi=10.1093/nar/gkr783|pmc=3258158|pmid=21948791}}</ref> 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.<ref>{{cite journal|last1=Brennan|first1=C. M.|last2=Steinz|first2=J. A.|title=HuR and MRNA Stability|journal=Cellular and Molecular Life Sciences|date=Feb 2001|volume=58|issue=2|pages=266–277|doi=10.1007/pl00000854|pmid=11289308|s2cid=35201269|pmc=11146503}}</ref> 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.<ref>{{Cite journal |last1=Cook |first1=Melissa E. |last2=Bradstreet |first2=Tara R. |last3=Webber |first3=Ashlee M. |last4=Kim |first4=Jongshin |last5=Santeford |first5=Andrea |last6=Harris |first6=Kevin M. |last7=Murphy |first7=Maegan K. |last8=Tran |first8=Jennifer |last9=Abdalla |first9=Nada M. |last10=Schwarzkopf |first10=Elizabeth A. |last11=Greco |first11=Suellen C. |last12=Halabi |first12=Carmen M. |last13=Apte |first13=Rajendra S. |last14=Blackshear |first14=Perry J. |last15=Edelson |first15=Brian T. |date=2022-10-28 |title=The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses |journal=Science Immunology |volume=7 |issue=76 |article-number=eabo0981 |doi=10.1126/sciimmunol.abo0981 |issn=2470-9468 |pmc=9832469 |pmid=36269839}}</ref> Deficient mice have also indicated a protective role for ZFP36 ARE binding proteins via regulating cytokine levels in the thymic microenvironment, thereby preventing thymic involution.<ref>{{Cite journal |last=Han |first=Jianxun |last2=Golzari-Sorkheh |first2=Mahdieh |last3=Rajan |first3=Vinothkumar |last4=Zúñiga-Pflücker |first4=Juan Carlos |date=2026-03-16 |title=RNA-binding proteins Zfp36l1 and Zfp36l2 protect against premature thymic involution |journal=Cellular & Molecular Immunology |doi=10.1038/s41423-026-01399-7 |issn=2042-0226 |pmid=41840035|doi-access=free }}</ref> Additional potential problems have been listed below:<ref name="Ref1" /> * 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 * ZFP36 ARE binding proteins have been reported to play a critical role in mitigating postsurgical pain by tamping down peripheral, central and systemic inflammatory responses.<ref>{{Cite journal |last=Guha |first=Abhishek |last2=Sorge |first2=Robert E. |last3=Si |first3=Ying |last4=Smith |first4=Reed |last5=Baig |first5=Sohail M. |last6=Husain |first6=Mohammed Amir |last7=Totsch |first7=Stacie K. |last8=Piper |first8=Ava M. |last9=Blackshear |first9=Perry J. |last10=King |first10=Peter H. |date=2025-11-26 |title=Myeloid-specific tristetraprolin mitigates postsurgical incisional pain by suppressing proinflammatory responses |journal=Inflammation Research|volume=74 |issue=1 |page=172 |doi=10.1007/s00011-025-02141-1 |issn=1420-908X |pmc=12657561 |pmid=41296045}}</ref>
==References== {{reflist}}
==External links== *[http://www.jimmunol.org/content/189/1/3.long/ Review of original publication discovering AU-rich elements] *[http://www.jimmunol.org/content/189/1/5.long/ Pillars link to original 1986 Cell publication discovering AU-rich elements] *[http://www.sciencemag.org/cgi/content/abstract/245/4920/852 mRNA Translational blockade by AU-rich elements] *[https://web.archive.org/web/20080207173029/http://transterm.otago.ac.nz/RNAMotif.html Brief introduction to mRNA regulatory elements] *[https://web.archive.org/web/20080307031756/http://brp.kfshrc.edu.sa/ARED/ ARED: AU-rich element database] *[https://web.archive.org/web/20081014051538/http://mrna.otago.ac.nz/cgi-bin/tt_data_browse/RNAMotif?PatID=T0024 Transterm page for AU-Rich Element] *[https://archive.today/20121127121738/http://rna.tbi.univie.ac.at/cgi-bin/AREsite.cgi AREsite: An online resource for the analysis of AREs]
{{DEFAULTSORT:Au-Rich Element}} Category:RNA Category:Gene expression Category:Cis-regulatory RNA elements