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.[1] The function of AREs was originally discovered by Shaw and Kamen in 1986.[2]

AREs are defined as a region with frequent adenine and uridine bases in a mRNA. They usually target the mRNA for rapid degradation.[3][2] 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] 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.[4][5]

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.[6] 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.[7] HuD (also called ELAVL4) binds to AREs and increases the half-life of ARE-bearing mRNAs in neurons during brain development and plasticity.[8]

AREsite—a database for ARE containing genes—has recently been developed with the aim to provide detailed bioinformatic characterization of AU-rich elements.[9]

  1. ^ 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.
  2. ^ a b 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.
  3. ^ C 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. PMC 1325018. PMID 16391004.
  4. ^ Kontoyiannis, D.; Pasparakis, M.; Pizarro, T. T.; Cominelli, F.; Kollias, G. (March 1999). "Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies". Immunity. 10 (3): 387–398. doi:10.1016/s1074-7613(00)80038-2. ISSN 1074-7613. PMID 10204494.
  5. ^ Arao, Yukitomo; Stumpo, Deborah J.; Hoenerhoff, Mark J.; Tighe, Robert M.; Yu, Yen-Rei; Sutton, Deloris; Kashyap, Amogh; Beerman, Isabel; Blackshear, Perry J. (August 2023). "Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA". FASEB Journal. 37 (8): e23100. doi:10.1096/fj.202300757R. ISSN 1530-6860. PMC 11078221. PMID 37462673.
  6. ^ 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.
  7. ^ Q, Jing; S, Huang; S, Guth; T, Zarubin; A, Motoyama; J, Chen; F, Di Padova; Sc, Lin; H, Gram; J, Han (2005-03-11). "Involvement of microRNA in AU-rich element-mediated mRNA instability". Cell. 120 (5): 623–634. doi:10.1016/j.cell.2004.12.038. ISSN 0092-8674. PMID 15766526.
  8. ^ Nora Perrone-Bizzozero & 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.
  9. ^ 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.