Cytoplasmic polyadenylation element

The cytoplasmic polyadenylation element (CPE) is a sequence element found in the 3' untranslated region of messenger RNA. While several sequence elements are known to regulate cytoplasmic polyadenylation, CPE is the best characterized.[1] The most common CPE sequence is UUUUAU, though there are other variations.[2] Binding of CPE binding protein (CPEB) to this region promotes the extension of the existing polyadenine tail and, in general, activation of the mRNA for protein translation. This elongation occurs after the mRNA has been exported from the nucleus to the cytoplasm. A longer poly(A) tail attracts more cytoplasmic polyadenine binding proteins (PABPs) which interact with several other cytoplasmic proteins that encourage the mRNA and the ribosome to associate.[1] The lengthening of the poly(A) tail thus has a role in increasing translational efficiency of the mRNA. The polyadenine tails are extended from approximately 40 bases to 150 bases.[2]

Cytoplasmic polyadenylation should be distinguished from nuclear polyadenlyation; cytoplasmic polyadenylation occurs in the cytoplasm in specific mRNAs as opposed to occurring in the nucleus and affecting almost all eukaryotic mRNAs.[3] Among other functions, a prominent role for the CPE has been identified in oogenesis, spermatogenesis, mitosis, and the growth of new synapses[4][5][6] The role of the CPE was first characterized in Xenopus oocytes and embryos but recent research has identified roles for the CPE in somatic cells.[1][7] Some proto-oncogene mRNAs have been shown to contain CPEs. One such gene is Myc. The level of production of the different CPEB proteins determines whether the expression of Myc leads to tumor formation.[8] The tumor suppressor gene TP53 has also been shown to be regulated by a CPE. Cell lines that do not produce CPEB show lower levels of the protein p53 and become immortal instead of showing senescence.[9]

The eCPE and the C-CPE are two other cytoplasmic polyadenylation elements that are found within embryos. The most common eCPE sequence is UUUUUUUUUUUU while the sequence of C-CPE is generally a very C rich region with the occasional U. All of these CPEs have in common that their effectiveness in promoting the extension of the poly(A) tail depends on their proximity to the poly(A) signal.[1] Optimally, they should be within 25 nucleotides but can be as far as 100 nucleotides from the poly(A) signal.[10] Alternately, CPEs can cause translation repression if two CPE sequences are located within 50 nucleotides of each other within the 3’ UTR.[1] The highest amounts of repression are seen when the two CPEs are 10 to 12 nucleotides apart. If the CPE has a nonconsensus sequence, a nearby Pumilio-binding element (PBE) is necessary for translational activation to result. If the CPE has a consensus sequence, the presence of the PBE can double the resulting translational activation.[10] The CPE is not the only cis-acting element to regulate 3'UTR processing as alternative polyadenylation (APA) signals, microRNA target sites, and AU rich elements (ARE) also have roles in determining the length of the poly(A) tail.[11]

Research

Research into the CPE has focused on further elucidating its role in translational regulation and its role in development. Research on Aplysia neurons has shown that the CPE has a role in regulating memory formation. When long-term memories are being formed, CPEs found in neuronal actin mRNAs allow the up-regulation of this protein. Increased concentrations of actin allow new synapses to grow, allowing memory storage.[12]

A study done on mRNA regulation during oogenesis in Drosophila has revealed that the CPE and CPE binding proteins help control the timing of protein production during development. Oocytes transcribe a large portion of their mRNA at one time and rely on other control mechanisms to determine the timing of protein production. The study showed that mRNAs that are a target of the CPEB WISP show significant polyA tail extension but not an increased number of mRNA transcripts.[13]

References
  1. Charlesworth, Amanda; Meijer, Hedda A.; de Moor, Cornelia H. (2013-07-01). "Specificity factors in cytoplasmic polyadenylation". Wiley Interdisciplinary Reviews: RNA. 4 (4): 437–461. doi:10.1002/wrna.1171. ISSN 1757-7012. PMC 3736149. PMID 23776146.
  2. Ivshina, Maria; Lasko, Paul; Richter, Joel D. (11 October 2014). "Cytoplasmic Polyadenylation Element Binding Proteins in Development, Health, and Disease". Annual Review of Cell and Developmental Biology. 30 (1): 393–415. doi:10.1146/annurev-cellbio-101011-155831. PMID 25068488.
  3. Hunt, Arthur G.; Xu, Ruqiang; Addepalli, Balasubrahmanyam; Rao, Suryadevara; Forbes, Kevin P.; Meeks, Lisa R.; Xing, Denghui; Mo, Min; Zhao, Hongwei (2008-01-01). "Arabidopsis mRNA polyadenylation machinery: comprehensive analysis of protein-protein interactions and gene expression profiling". BMC Genomics. 9: 220. doi:10.1186/1471-2164-9-220. ISSN 1471-2164. PMC 2391170. PMID 18479511.
  4. de Moor, C.H.; Richter, J.D. (1999). "Cytoplasmic polyadenylation mediate masking and unmasking of cyclin B1 mRNA". EMBO J. 18 (8): 2294–2303. doi:10.1093/emboj/18.8.2294. PMC 1171312. PMID 10205182.
  5. Luitjens, C; Gallegos, M; Kraemer, B; Kimble, J; Wickens, M (2000). "CPEB proteins control two key steps in spermatogenesis in C. elegans". Genes Dev. 14 (20): 2596–609. doi:10.1101/gad.831700. PMC 316992. PMID 11040214.
  6. Villalba, Ana; Coll, Olga; Gebauer, Fátima (2011). "Cytoplasmic polyadenylation and translational control". Current Opinion in Genetics & Development. 21 (4): 452–457. doi:10.1016/j.gde.2011.04.006. PMID 21536428.
  7. Rutledge, Charlotte E.; Lau, Ho-Tak; Mangan, Hazel; Hardy, Linda L.; Sunnotel, Olaf; Guo, Fan; MacNicol, Angus M.; Walsh, Colum P.; Lees-Murdock, Diane J. (2014-02-20). "Efficient Translation of Dnmt1 Requires Cytoplasmic Polyadenylation and Musashi Binding Elements". PLOS ONE. 9 (2): e88385. doi:10.1371/journal.pone.0088385. ISSN 1932-6203. PMC 3930535. PMID 24586322.
  8. Chen, Yun; Tsai, Ya-Hui; Tseng, Sheng-Hong (2016-11-01). "Regulation of the Expression of Cytoplasmic Polyadenylation Element Binding Proteins for the Treatment of Cancer". Anticancer Research. 36 (11): 5673–5680. doi:10.21873/anticanres.11150. ISSN 0250-7005. PMID 27793888.
  9. Burns, David M.; Richter, Joel D. (2008-12-15). "CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation". Genes & Development. 22 (24): 3449–3460. doi:10.1101/gad.1697808. ISSN 0890-9369. PMC 2607074. PMID 19141477.
  10. Piqué, Maria; López, José Manuel; Foissac, Sylvain; Guigó, Roderic; Méndez, Raúl (2008). "A Combinatorial Code for CPE-Mediated Translational Control". Cell. 132 (3): 434–448. doi:10.1016/j.cell.2007.12.038. PMID 18267074.
  11. Zhang, Xiaokan; Virtanen, Anders; Kleiman, Frida E. (2010-11-15). "To polyadenylate or to deadenylate". Cell Cycle. 9 (22): 4437–4449. doi:10.4161/cc.9.22.13887. ISSN 1538-4101. PMC 3048043. PMID 21084869.
  12. Liu, Jinming; Schwartz, James H. (2003-01-03). "The cytoplasmic polyadenylation element binding protein and polyadenylation of messenger RNA in Aplysia neurons". Brain Research. 959 (1): 68–76. doi:10.1016/s0006-8993(02)03729-0. ISSN 0006-8993. PMID 12480159.
  13. Cui, Jun; Sartain, Caroline V.; Pleiss, Jeffrey A.; Wolfner, Mariana F. (2013-11-01). "Cytoplasmic polyadenylation is a major mRNA regulator during oogenesis and egg activation in Drosophila". Developmental Biology. 383 (1): 121–131. doi:10.1016/j.ydbio.2013.08.013. PMC 3821703. PMID 23978535.
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