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 proteins (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, miRNAs may also bind to some of them.[4]HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.[5]
AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.[6]
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.[2]
Mechanism of ARE-mediated decayEdit
AREs are recognized by RNA binding proteins such as tristetraprolin (TTP), AUF1, and Hu Antigen R (HuR).[7] 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.[7]
The proposed mechanism for which ARE elements function & control sequencing.
TTP's expression is rapidly induced by insulin.[8] Immunoprecipitation experiments have shown that TTP co-precipitates with an exosome, suggesting that it helps recruit exosomes to the mRNA containing AREs.[9] 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.[10] 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.[11]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.
DiseaseEdit
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. Some of these problems have been listed below:[7]
The c-fos gene produces a transcription factor that is activated in several cancers, and it lacks the ARE elements.
c-myc gene, also responsible for producing transcription factors found in several cancers, has also been reported to lack the ARE elements.
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
ReferencesEdit
^ abChen, 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. PMID 8578590.
^ abC Barreau, L Paillard & H B Osborne (2006). "AU-rich elements and associated factors: are there unifying principles?". Nucleic Acids Res. 33 (22): 7138–7150. doi:10.1093/nar/gki1012. PMC1325018. PMID 16391004.
^Shaw G, Kamen R (August 1986). "A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation". Cell. 46 (5): 659–667. doi:10.1016/0092-8674(86)90341-7. PMID 3488815. S2CID 40332253.
^Federico Bolognani & Nora Perrone-Bizzozero (2008). "RNA-protein interactions and control of mRNA stability in neurons". J Neurosci Res. 86 (3): 481–489. doi:10.1002/jnr.21473. PMID 17853436. S2CID 27076039.
^Gruber AR, Fallmann J, Kratochvill F, Kovarik P, Hofacker IL (2011). "AREsite: a database for the comprehensive investigation of AU-rich elements". Nucleic Acids Res. 39 (Database issue): D66–9. doi:10.1093/nar/gkq990. PMC3013810. PMID 21071424.
^ abcElliott, David; Ladomery, Michael (2011). Stability and Degradation of mRNA. Oxford: Oxford UP. p. 312.
^Cao, H; JF Jr, Urban; RA, Anderson (Apr 2008). "Insulin Increases Tristetraprolin and Decreases VEGF Gene Expression in Mouse 3T3-L1 Adipocytes". Obesity. 16 (6): 1208–1218. doi:10.1038/oby.2008.65. PMID 18388887. S2CID 19149343.
^Tiedje, Christopher; Kotlyarov, Alexey; Gaestel, Matthias (2010). "Molecular Mechanisms of Phosphorylation-regulated TTP (tristetraprolin) Action and Screening for Further TTP-interacting Proteins" (PDF). Biochemical Society Transactions. 38 (6): 1632–1637. doi:10.1042/bst0381632. PMID 21118139.
^Dai, Weijun; Zhang, Gen; Makeyev, Eugene V. (24 Sep 2011). "RNA-binding Protein HuR Autoregulates Its Expression by Promoting Alternative Polyadenylation Site Usage". Nucleic Acids Research. 40 (2): 787–800. doi:10.1093/nar/gkr783. PMC3258158. PMID 21948791.
^Brennan, C. M.; Steinz, J. A. (Feb 2001). "HuR and MRNA Stability". Cellular and Molecular Life Sciences. 58 (2): 266–277. doi:10.1007/pl00000854. PMID 11289308. S2CID 35201269.
External linksEdit
Review of original publication discovering AU-rich elements
Pillars link to original 1986 Cell publication discovering AU-rich elements
mRNA Translational blockade by AU-rich elements
AREsite: An online resource for the analysis of AREs
October 15, 2023
rich, element, adenylate, uridylate, rich, elements, ares, found, untranslated, region, many, messenger, rnas, mrnas, that, code, proto, oncogenes, nuclear, transcription, factors, cytokines, ares, most, common, determinants, stability, mammalian, cells, ares,. 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 1 AREs are defined as a region with frequent adenine and uridine bases in a mRNA They usually target the mRNA for rapid degradation 2 3 ARE directed mRNA degradation is influenced by many exogenous factors including phorbol esters calcium ionophores 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 1 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 proteins 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 miRNAs may also bind to some of them 4 HuD also called ELAVL4 binds to AREs and increases the half life of ARE bearing mRNAs in neurons during brain development and plasticity 5 AREsite a database for ARE containing genes has recently been developed with the aim to provide detailed bioinformatic characterization of AU rich elements 6 Contents 1 Classifications 2 Mechanism of ARE mediated decay 3 Disease 4 References 5 External linksClassifications EditClass 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 2 Mechanism of ARE mediated decay EditAREs are recognized by RNA binding proteins such as tristetraprolin TTP AUF1 and Hu Antigen R HuR 7 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 7 nbsp The proposed mechanism for which ARE elements function amp control sequencing TTP s expression is rapidly induced by insulin 8 Immunoprecipitation experiments have shown that TTP co precipitates with an exosome suggesting that it helps recruit exosomes to the mRNA containing AREs 9 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 10 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 11 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 EditProblems 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 Some of these problems have been listed below 7 The c fos gene produces a transcription factor that is activated in several cancers and it lacks the ARE elements c myc gene also responsible for producing transcription factors found in several cancers has also been reported to lack the ARE elements 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 AREReferences Edit a b 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 PMID 8578590 a b C Barreau L Paillard amp H B Osborne 2006 AU rich elements and associated factors are there unifying principles Nucleic Acids Res 33 22 7138 7150 doi 10 1093 nar gki1012 PMC 1325018 PMID 16391004 Shaw G Kamen R August 1986 A conserved AU sequence from the 3 untranslated region of GM CSF mRNA mediates selective mRNA degradation Cell 46 5 659 667 doi 10 1016 0092 8674 86 90341 7 PMID 3488815 S2CID 40332253 Federico Bolognani amp Nora Perrone Bizzozero 2008 RNA protein interactions and control of mRNA stability in neurons J Neurosci Res 86 3 481 489 doi 10 1002 jnr 21473 PMID 17853436 S2CID 27076039 Nora Perrone Bizzozero amp Federico Bolognani 2002 Role of HuD and other RNA binding proteins in neural development and plasticity J Neurosci Res 68 2 121 126 doi 10 1002 jnr 10175 PMID 11948657 Gruber AR Fallmann J Kratochvill F Kovarik P Hofacker IL 2011 AREsite a database for the comprehensive investigation of AU rich elements Nucleic Acids Res 39 Database issue D66 9 doi 10 1093 nar gkq990 PMC 3013810 PMID 21071424 a b c Elliott David Ladomery Michael 2011 Stability and Degradation of mRNA Oxford Oxford UP p 312 Cao H JF Jr Urban RA Anderson Apr 2008 Insulin Increases Tristetraprolin and Decreases VEGF Gene Expression in Mouse 3T3 L1 Adipocytes Obesity 16 6 1208 1218 doi 10 1038 oby 2008 65 PMID 18388887 S2CID 19149343 Tiedje Christopher Kotlyarov Alexey Gaestel Matthias 2010 Molecular Mechanisms of Phosphorylation regulated TTP tristetraprolin Action and Screening for Further TTP interacting Proteins PDF Biochemical Society Transactions 38 6 1632 1637 doi 10 1042 bst0381632 PMID 21118139 Dai Weijun Zhang Gen Makeyev Eugene V 24 Sep 2011 RNA binding Protein HuR Autoregulates Its Expression by Promoting Alternative Polyadenylation Site Usage Nucleic Acids Research 40 2 787 800 doi 10 1093 nar gkr783 PMC 3258158 PMID 21948791 Brennan C M Steinz J A Feb 2001 HuR and MRNA Stability Cellular and Molecular Life Sciences 58 2 266 277 doi 10 1007 pl00000854 PMID 11289308 S2CID 35201269 External links EditReview of original publication discovering AU rich elements Pillars link to original 1986 Cell publication discovering AU rich elements mRNA Translational blockade by AU rich elements Brief introduction to mRNA regulatory elements ARED AU rich element database Transterm page for AU Rich Element AREsite An online resource for the analysis of AREs Retrieved from https en wikipedia org w index php title AU rich element amp oldid 1092810979, wikipedia, wiki, book, books, library,
