The cytoplasmic polyadenylation element binding (CPEB) proteins are sequence-specific mRNA binding proteins that control translation in development, health, and disease. CPEB1, the founding member of this family, has become an important model for illustrating general principles of translational control by cytoplasmic polyadenylation in gametogenesis, cancer etiology, synaptic plasticity, learning, and memory. Although the biological functions of the other members of this protein family in vertebrates are just beginning to emerge, it is already evident that they, too, mediate important processes, such as cancer etiology and higher cognitive function. In Drosophila, the CPEB proteins Orb and Orb2 play key roles in oogenesis and in neuronal function, as do related proteins in Caenorhabditis elegans and Aplysia. We review the biochemical features of the CPEB proteins, discuss their activities in several biological systems, and illustrate how understanding CPEB activity in model organisms has an important impact on neurological disease.

The cytoplasmic messenger ribonucleoprotein particles of mammalian somatic cells contain the protein YB-1, also called p50, as a major core component. YB-1 is multifunctional and involved in regulation of mRNA transcription and translation. Our previous studies demonstrated that YB-1 stimulates initiation of translation in vitro at a low YB-1/mRNA ratio, whereas an increase of YB-1 bound to mRNA resulted in inhibition of protein synthesis in vitro and in vivo. Here we show that YB-1-mediated translation inhibition in a rabbit reticulocyte cell-free system is followed by a decay of polysomes, which is not a result of mRNA degradation or its functional inactivation. The inhibition does not change the ribosome transit time, and therefore, it affects neither elongation nor termination of polypeptide chains and only occurs at the stage of initiation. YB-1 induces accumulation of mRNA in the form of free messenger ribonucleoprotein particles, i.e. it blocks mRNA association with the small ribosomal subunit. The accumulation is accompanied by eukaryotic initiation factor eIF4G dissociation from mRNA. The C-terminal domain of YB-1 is responsible for inhibition of translation as well as the disruption of mRNA interaction with eIF4G.All mRNAs in eukaryotic cells are associated with proteins and form messenger ribonucleoprotein particles (mRNPs) 1 (1-6). Some mRNA-associated proteins exhibit specificity for certain mRNA(s); others are universal. To date, two universal major proteins of cytoplasmic mRNPs tightly bound to mRNA are well characterized. One of them is poly(A)-binding protein that stabilizes mRNA (7, 8) and promotes protein synthesis at the initiation stage (9, 10). It is suggested that the protein biosynthesis promotion occurs due to binding of multimerized poly(A)-binding protein associated with poly(A) to eIF4G and 1) mRNA cyclization and facilitation of ribosomal recycling (11, 12) and/or 2) a conformational change in eIF4F and an increase in affinity of eIF4E for the 5Ј-cap (13).The other common mRNP component is YB-1, a 36-kDa protein with abnormal mobility in SDS gel electrophoresis that is typical for this 50-kDa protein (14 -16). According to its primary structure, YB-1 from rabbit reticulocytes was identified as a member of the Y-box (YB) transcription factor family: it was virtually identical (ϳ98% identity) to human YB-1. YB-1 has been shown to participate in different steps of mRNA biogenesis, including mRNA transcription, processing, and transport from the nucleus into the cytoplasm (5, 17, 18) where it can regulate mRNA localization, translation, and mRNA stability (15,16,19). YB-1 displays DNA and RNA melting, annealing, and strand exchange activities, which probably underlies many functions of the YB protein family (20,21).The characteristic feature of these proteins is a central, highly conserved, cold shock domain (CSD) that consists of 80 amino acid residues and exhibits 43% identity to the major Escherichia coli cold shock protein CspA (4, 5). CSD comprises a five-stranded ␤-barrel with RNP ...

Fragile X Syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of Fmr1, which encodes the translational repressor protein FMRP. FMRP and CPEB, an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs, and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1-/y Cpeb−/− double knockout mice displayed significant amelioration of biochemical, morphological, electrophysiological, and behavioral phenotypes associated with FXS. Acute depletion of CPEB in the hippocampus of Fmr1 -/y mice rescued working memory deficits, demonstrating reversal of this FXS phenotype in adults. Finally, we find that FMRP and CPEB balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS, and that the maintenance of this homeostasis by FMRP and CPEB is necessary for normal neurologic function.

Cytoplasmic polyadenylation element-binding protein (CPEB) is; however, the mRNAs encoding these proteins are unlikely targets of CPEB since their expression is the same in wild-type and KO MEFs. Conversely, Ras cannot induce senescence in MEFs lacking CPEB, suggesting that it may lie upstream of CPEB. One target of CPEB regulation is myc mRNA, whose unregulated translation in the KO MEFs may cause them to bypass senescence. Thus, CPEB appears to act as a translational repressor protein to control myc translation and resulting cellular senescence.[Keywords: Senescence; CPEB; translational control] Supplemental material is available at http://www.genesdev.org.

The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.