CPEB: a life in translation
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.Trends in Biochemical Sciences (Impact Factor: 11.23). 07/2007; 32(6):279-85. DOI: 10.1016/j.tibs.2007.04.004
Nearly two decades ago, Xenopus oocytes were found to contain mRNAs harboring a small sequence in their 3' untranslated regions that control cytoplasmic polyadenylation and translational activation during development. This cytoplasmic polyadenylation element (CPE) is the binding platform for CPE-binding protein (CPEB), which promotes polyadenylation-induced translation. Since then, the biochemistry and biology of CPEB has grown rather substantially: mechanistically, CPEB nucleates a complex of factors that regulates poly(A) elongation through, of all things, a deadenylating enzyme; biologically, CPEB mediates many processes including germ-cell development, cell division and cellular senescence, and synaptic plasticity and learning and memory. These observations underscore the growing complexities of CPEB involvement in cell function.
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- "Using an in vitro RNA pull-down assay and a series of small deletions and nucleotide substitutions of the 3 0 UTR, we identified two sequence elements, UCCACCUU/G (Mutation1 or M1) and UUUUGU (Mutation2 or M2), that are involved in Orb2 recruitment to Tequila 3 0 UTR (Figures 1B and S1B). The M2 sequence is analogous to canonical CPEB binding element UUUUAU (Richter, 2007), and mutation of UUUUGU to GCUUGU (M2P) or deletion of four U residues (DM2) significantly reduced both monomeric and oligomeric Orb2 recruitment (Figures 1B and S1B). A U/CUUU/GU sequence motif, similar to M2 sequence, is also detected in the 3 0 UTR of Tequila gene of other Drosophila species (Figure S1C) as well as in other Orb2 targets (Mastushita-Sakai et al., 2010). "
ABSTRACT: Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory.
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- "In contrast, CPEBs extend the poly A tail and the length of mRNA, facilitating the activation and translation of dormant mRNA, generating the cell signaling cascade, and inducing abnormal mRNA translation. Furthermore, CPEBs significantly control aggravating cancerization by playing crucial roles in cell aging and synaptic plasticity (Richter, 2007; Burns and Richter, 2008), and thus are important in the onset, proliferation, invasion, and metastasis of glioma. Hence, it is feasible that controlling CPEBs is of great significance for glioma treatment. "
ABSTRACT: Glioma stem cells derived from primary cultures were divided into an experiment group, a control group, and a blank group and subjected to cytoplasmic polyadenilation element-binding protein (CPEBs) interference, transfection with empty vector, and normal culture, respectively, to compare their invasion abilities. Western blotting showed that siRNA-3 had the strongest interfering effect on CPEBs. CPEBs were expressed in the experiment group with green fluorescence at an expression rate of over 70%. Significantly lower CPEB expression was observed in the experiment group compared to in the control and blank groups (P < 0.05). After 48-h treatment, the apoptotic rate in the experiment group was 21.43%, which was significantly higher than that in the blank (0.51%) and control (1.43%) groups (P < 0.05). After 3 days of treatment, the experiment group grew significantly more slowly than did the control and blank groups (P < 0.05). The transwell invasion assay showed that significantly fewer cells in the experiment group penetrated the membrane than did cells in the control and blank groups (P < 0.05). After CPEB interference, the growth, proliferation, and invasion of glioma stem cells were substantially inhibited, providing support for targeted therapy of glioma and for improving prognosis.
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- "Cytoplasmic polyadenylation element binding (CPEB) proteins act sequentially in poly(A) tail shortening and lengthening through the recruitment of deadenylases and poly(A) polymerases (Richter, 2007). They bind to UArich short sequences, referred to as cytoplasmic polyadenylation elements (CPEs), located within 3 0 UTRs of their target mRNAs (Piqué et al., 2008;Richter, 2007). CPEB1 has been mostly studied for its implication in vertebrate oocyte maturation, where it is involved in translational repression through the recruitment of PARN deadenylase in immature oocytes and in translational activation through an interaction with Gld2 poly(A) polymerase during maturation (Igea and Mé ndez, 2010;Kim and Richter, 2006). "
ABSTRACT: Drosophila Orb, the homolog of vertebrate CPEB, is a key translational regulator involved in oocyte polarity and maturation through poly(A) tail elongation of specific mRNAs. orb also has an essential function during early oogenesis that has not been addressed at the molecular level. Here, we show that orb prevents cell death during early oogenesis, thus allowing oogenesis to progress. It does so through the repression of autophagy by directly repressing, together with the CCR4 deadenylase, the translation of Autophagy-specific gene 12 (Atg12) mRNA. Autophagy and cell death observed in orb mutant ovaries are reduced by decreasing Atg12 or other Atg mRNA levels. These results reveal a role of Orb in translational repression and identify autophagy as an essential pathway regulated by Orb during early oogenesis. Importantly, they also establish translational regulation as a major mode of control of autophagy, a key process in cell homeostasis in response to environmental cues.