CPEB4 Is a Cell Survival Protein Retained in the Nucleus upon Ischemia or Endoplasmic Reticulum Calcium Depletion

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2377, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2010; 30(24):5658-71. DOI: 10.1128/MCB.00716-10
Source: PubMed


The RNA binding protein CPEB (cytoplasmic polyadenylation element binding) regulates cytoplasmic polyadenylation and translation in germ cells and the brain. In neurons, CPEB is detected at
postsynaptic sites, as well as in the cell body. The related CPEB3 protein also regulates translation in neurons, albeit probably
not through polyadenylation; it, as well as CPEB4, is present in dendrites and the cell body. Here, we show that treatment
of neurons with ionotropic glutamate receptor agonists causes CPEB4 to accumulate in the nucleus. All CPEB proteins are nucleus-cytoplasm
shuttling proteins that are retained in the nucleus in response to calcium-mediated signaling and alpha-calcium/calmodulin-dependent
kinase protein II (CaMKII) activity. CPEB2, -3, and -4 have conserved nuclear export signals that are not present in CPEB.
CPEB4 is necessary for cell survival and becomes nuclear in response to focal ischemia in vivo and when cultured neurons are deprived of oxygen and glucose. Further analysis indicates that nuclear accumulation of CPEB4
is controlled by the depletion of calcium from the ER, specifically, through the inositol-1,4,5-triphosphate (IP3) receptor,
indicating a communication between these organelles in redistributing proteins between subcellular compartments.

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    • "CPEBs2-4 have 96% and ∼25–35% identity in the C-terminal RNA-binding domain (RBD) and the N-terminal regulatory region, respectively, but they share 45% identity with CPEB1 only in the RBD region [17], [18]. CPEBs shuttle between nucleocytoplasmic compartments with longer retention in the cytoplasm where they regulate target RNA translation [19], [20], [21], [22]. Among them, only CPEB1 was reported to localize in SGs [23]. "
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    ABSTRACT: Stress granules (SGs) are compartmentalized messenger ribonucleoprotein particles (mRNPs) where translationally repressed mRNAs are stored when cells encounter environmental stress. Cytoplasmic polyadenylation element-binding protein (CPEB)4 is a sequence-specific RNA-binding protein and translational regulator. In keeping with the results obtained from the study of other RNA-binding proteins, we found CPEB4 localized in SGs in various arsenite-treated cells. In this study, we identified that Vinexin, a CPEB4-interacting protein, is a novel component of SGs. Vinexin is a SH3-domain-containing adaptor protein and affects cell migration through its association with Vinculin to localize at focal adhesions (FAs). Unexpectedly, Vinexin is translocated from FAs to SGs under arsenite-induced stress. The recruitment of Vinexin to SGs depends on its interaction with CPEB4 and influences SG formation and cell survival. Arsenite-activated c-Jun N-terminal kinase (JNK) signaling enhances the association between CPEB4 and Vinexin, which consequently facilitates SG localization of Vinexin. Taken together, this study uncovers a novel interaction between a translational regulator and an adaptor protein to influence SG assembly and cell survival.
    PLoS ONE 09/2014; 9(9):e107961. DOI:10.1371/journal.pone.0107961 · 3.23 Impact Factor
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    • "CPEB4 possesses the same sequence-binding specificity with CPEB2 and CPEB3 in vitro [2] but is functionally related to CPEB1 during cell cycle [8], [13]. Although it is conceivable that elimination of CPEB4 could have resulted in compensatory mechanisms through which another CPEB substitutes for memory function normally exerted by CPEB4, it is also possible that the abundant expression of CPEB4 in the hippocampus may have other functions except learning and memory, possibly like promoting neuronal survival after cerebral ischemia [16]. Further investigation is needed to uncover, if any, the nature of potential compensatory mechanisms or other abnormalities in the CPEB4 KO mice. "
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    ABSTRACT: Regulated RNA translation is critical to provide proteins needed to maintain persistent modification of synaptic strength, which underlies the molecular basis of long-term memory (LTM). Cytoplasmic polyadenylation element-binding proteins (CPEBs) are sequence-specific RNA-binding proteins and regulate translation in various tissues. All four CPEBs in vertebrates are expressed in the brain, including the hippocampal neurons, suggesting their potential roles in translation-dependent plasticity and memory. Although CPEB1 and CPEB3 have been shown to control specific kinds of hippocampus-related LTM, the role of CPEB2 and CPEB4 in learning and memory remains elusive. Thus, we generated CPEB4 knockout (KO) mice and analyzed them using several behavioral tests. No difference was found in the anxiety level, motor coordination, hippocampus-dependent learning and memory between the KO mice and their wild-type (WT) littermates. Electrophysiological recordings of multiple forms of synaptic plasticity in the Schaffer collateral pathway-CA1 neurons also showed normal responses in the KO hippocampal slices. Morphological analyses revealed that the CPEB4-lacking pyramidal neurons possessed slightly elongated dendritic spines. Unlike its related family members, CPEB1 and CPEB3, CPEB4 seems to be dispensable for hippocampus-dependent plasticity, learning and memory.
    PLoS ONE 12/2013; 8(12):e84978. DOI:10.1371/journal.pone.0084978 · 3.23 Impact Factor
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    • "Although the biological function of CPEB1 has been studied extensively, the function of CPEB4, a member of the CPEB2 subfamily, remains largely unexplored. It has been reported that CPEB4 acts as a cell survival protein in neurons [31] and regulates meiotic cells [25]. In pancreatic ductal cancer and neuroblastoma, the expression of CPEB4 is upregulated, driving the growth and invasion of cancer cells [27]. "
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    ABSTRACT: MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that are often found at chromosomal breakpoints and play a vital role in human cancer. Our previous study found that miR-550a, a frequently amplified miRNA on 7p14.3, was upregulated in hepatocellular carcinoma (HCC). However, the possible functions and molecular mechanisms of miR-550a in HCC remain unknown. In this study, gain-of-function and loss-of-function assays revealed that miR-550a markedly promoted HCC cell migration and invasion. In addition, we discovered that cytoplasmic polyadenylation element binding protein 4 (CPEB4) was a potential target of miR-550a in HCC. Further analyses showed that knockdown of CPEB4 expression significantly facilitated HCC cell migration and invasion, which phenocopied the effects of miR-550a on HCC cells. Moreover, a decrease in CPEB4 expression mediated miR-550a-induced liver cancer cell migration and invasion. Interestingly, CPEB4 is frequently downregulated in HCC, and its expression levels correlate with the overall survival of HCC patients. Together, these results suggested that this newly identified miR-550a-CPEB4 axis may be involved in HCC cell metastasis. Moreover, the expression levels of CPEB4 could be used to predict outcomes in HCC patients. Our findings provide novel potential targets for HCC therapy and prognosis.
    PLoS ONE 11/2012; 7(11):e48958. DOI:10.1371/journal.pone.0048958 · 3.23 Impact Factor
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