A Molecular Circuit Composed of CPEB-1 and c-Jun Controls Growth Hormone-Mediated Synaptic Plasticity in the Mouse Hippocampus

Zearfoss, N. Ruth; Alarcón, Juan Marcos; Trifilieff, Pierre; Kandel, Eric R.; Richter, Joel D.

doi:10.1523/jneurosci.1756-08.2008

Cited by 81 publications

(64 citation statements)

References 46 publications

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“…As a consequence of its regulation of mRNA expression, CPEB mediates germ cell development (15,16), neuronal synaptic plasticity (17)(18)(19)(20), and cellular senescence (21)(22)(23)(24). Several observations suggest that CPEB might also be involved in the immune response.…”

mentioning

confidence: 99%

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

Ivshina

Alexandrov

Vertii

et al. 2015

Molecular and Cellular Biology

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The cytoplasmic-element-binding (CPEB) protein is a sequence-specific RNA-binding protein that regulates cytoplasmic polyadenylation-induced translation. In mouse embryo fibroblasts (MEFs) lacking CPEB, many mRNAs encoding proteins involved in inflammation are misregulated. Correlated with this aberrant translation in MEFs, a macrophage cell line depleted of CPEB and treated with lipopolysaccharide (LPS) to stimulate the inflammatory immune response expresses high levels of interleukin-6 (IL-6), which is due to prolonged nuclear retention of NF-B. Two proteins involved in NF-B nuclear localization and IL-6 expression, IB␣ and transforming growth factor beta-activated kinase 1 (TAK1), are present at excessively low and high steadystate levels, respectively, in LPS-treated CPEB-depleted macrophages. However, only TAK1 has an altered synthesis rate that is CPEB dependent and CPEB/TAK1 double depletion alleviates high IL-6 production. Peritoneal macrophages isolated from CPEB knockout (KO) mice treated with LPS in vitro also have prolonged NF-B nuclear retention and produce high IL-6 levels. LPS-injected CPEB KO mice secrete prodigious amounts of IL-6 and other proinflammatory cytokines and exhibit hypersensitivity to endotoxic shock; these effects are mitigated when the animals are also injected with (5Z)-7-oxozeaenol, a potent and specific inhibitor of TAK1. These data show that CPEB control of TAK1 mRNA translation mediates the inflammatory immune response. Inflammation is triggered by bacterial pathogens, as well as lipopolysaccharide (LPS), a bacterial cell wall component that activates the transcription of multiple inflammatory response genes, including those for cytokines and chemokines (1, 2). Despite the importance of these inflammation mediators for host defense against infection, their excessive production can elicit organ failure and septic shock that results in lethality. Therefore, limitation of cytokine production is essential for the termination of inflammation and the prevention of endotoxic tissue damage (2).The production of inflammatory mediators is controlled at multiple levels, including transcription, translation, and protein stability (3). LPS promotes the nuclear import of NF-B (4) by indirectly regulating the activity of the IB kinase (IKK) complex, which phosphorylates IB␣, a factor that normally retains NF-B in the cytoplasm (5-7). Phosphorylated IB␣ is rapidly destroyed, thereby releasing NF-B to translocate to the nucleus and activate the transcription of target genes (8, 9). A proximal upstream LPSactivated factor is the Toll-like receptor, whose signaling pathway includes transforming growth factor beta-activated kinase 1 (TAK1), a mitogen-activated protein (MAP) kinase kinase kinase (10). TAK1 stimulation of p38 MAP kinase leads to IKK activity and NF-B import. LPS stimulation of TAK1 also triggers the stabilization of many mRNAs, which is dependent upon the interplay of several 3= untranslated region (UTR)-binding proteins such as those that associate with the AU-rich element (ARE) ...

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mentioning

confidence: 99%

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

Ivshina

Alexandrov

Vertii

et al. 2015

Molecular and Cellular Biology

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“…CPEB knockout mice (44) have deficiencies in synaptic plasticity, particularly, theta burst-induced long-term potentiation (LTP) (1,51), as well as in particular forms of hippocampal-dependent memories (3). Some of these CPEB-related functions may be related at least in part to its ability to direct CPE-containing RNA transport in dendrites (16), in addition to its regulation of translation (51).…”

mentioning

confidence: 99%

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

Kan

Oruganty-Das

Cooper-Morgan

et al. 2010

Molecular and Cellular Biology

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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.The cytoplasmic polyadenylation element binding (CPEB) protein, a sequence-specific RNA binding protein, is found in the cell body and at synapses of hippocampal and other neurons; in response to synaptic experience, CPEB promotes polyadenylation and translation (37,49,50). CPEB knockout mice (44) have deficiencies in synaptic plasticity, particularly, theta burst-induced long-term potentiation (LTP) (1, 51), as well as in particular forms of hippocampal-dependent memories (3). Some of these CPEB-related functions may be related at least in part to its ability to direct CPE-containing RNA transport in dendrites (16), in addition to its regulation of translation (51).In neurons, most of the CPEB-related proteins CPEB3 and CPEB4 are found in the cell soma. However, a relatively small amount of these proteins is localized to synaptic regions and cofractionates with postsynaptic density (PSD) proteins, suggesting possible roles in RNA translation and/or localization (17). While investigating the possible translocation of CPEB3 and -4 to dendritic spines in response to N-methyl-D-aspartate receptor (NMDAR) activation, as is the case with the fragile X mental retardation protein (FMRP) (11), we noticed a surprising relocalization of CPEB4 from the cell soma to the nucleus. While the treatment of neurons with ionotropic glutamate receptor-activating agents, such as glutamate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), as well as NMDA, induced nuclear localization of CPEB4, 3,5-dihydroxyphenylglycine (DHPG), an agonist of the metabotropic glutamate receptors, did not. CPEB4 remained cytoplasmic when calcium/calmodulin-dependent protein kinase II (CaMKII) activity was inhibited, suggesting a link between calcium levels and nuclear i...

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“…It has also been shown that c-jun mRNA translation is regulated by CPEB and that growth hormone (GH) transcription via c-jun could mediate synaptic plasticity in the mouse hippocampus. 104 Interestingly, ARE-containing mRNAs are regulated by a polyadenylation/deadenylation mechanism both in the cytoplasm and in the nucleus. 49,104 It has been shown that CPEB possesses a self-perpetuating prion-like behavior in invertebrates, and that the aggregated form of CPEB remains activated for a long period of time upregulating cytoplasmic polyadenylation and translation locally in dendrites.…”

Section: Cis-elements Involved In Polyadenylation/deadenylationmentioning

confidence: 99%

“…104 Interestingly, ARE-containing mRNAs are regulated by a polyadenylation/deadenylation mechanism both in the cytoplasm and in the nucleus. 49,104 It has been shown that CPEB possesses a self-perpetuating prion-like behavior in invertebrates, and that the aggregated form of CPEB remains activated for a long period of time upregulating cytoplasmic polyadenylation and translation locally in dendrites. [105][106][107] Further studies are required to determine if there is a functional connection between CPEB prion-like structure and its translational regulatory functions in different organisms.…”

Section: Cis-elements Involved In Polyadenylation/deadenylationmentioning

confidence: 99%

To polyadenylate or to deadenylate

2010

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A Molecular Circuit Composed of CPEB-1 and c-Jun Controls Growth Hormone-Mediated Synaptic Plasticity in the Mouse Hippocampus

Cited by 81 publications

References 46 publications

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

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

To polyadenylate or to deadenylate

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