Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent β-Catenin mRNA Translation in Developing Hippocampal Neurons

Kundel, Mitchell; Jones, Kendrick J.; Shin, Chan Young; Wells, David G.

doi:10.1523/jneurosci.2910-08.2009

Cited by 51 publications

(47 citation statements)

References 53 publications

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“…Our data suggest a model in which CPE-containing mRNA are bound by CPEB1 in the nucleus and trafficked to the periphery of the cell and subsequently translated. In support of this, studies in hippocampal neurons have shown expression of the RNA-binding domain of CPEB1 (akin to our DN-CPEB1-GFP) is primarily localized to the cell body (1,7) and that the CPEB1-RBD construct is no longer able to bind to dyenin and kinesin (1), the motor proteins thought to be responsible for CPEB1 transport.…”

Section: Discussionmentioning

confidence: 68%

“…The CPE sequences used for the reporter were based on the b-catenin 3 0 -UTR, a well-characterized target of CPEB1 (3,7). Approximately, 250 nucleotides of the 900-nucleotide b-catenin, 3 0 -UTR was amplified from mouse cDNA as previously described (7).…”

Section: Reporter Construct Generationmentioning

confidence: 99%

“…The mutant CPEB1 protein we termed DN-CPEB1 (dominant negative-CPEB1) because it binds specifically to CPEB1 targets, blocking the endogenous CPEB1 from binding, and reduces the translation of bound mRNA (1,3,7). Our rationale for using this approach was predicated on our goal of turning off CPEB1-mediated mRNA translation.…”

Section: Introductionmentioning

confidence: 99%

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CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. Mol Cancer Res; 11(2); 149-60. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 68%

Section: Reporter Construct Generationmentioning

confidence: 99%

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CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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“…Triggered by an external stimulus, CPEBs are phosphorylated, which stimulates growth cone translation; conceivably, the CPEB phosphorylation could be a limiting factor in ALCAM translation. CPEB phosphorylation is crucial for appropriate growth cone reactions to the environment (Brittis et al, 2002;Kundel et al, 2009) and thereby might also be important for the impact of ALCAM on axonal navigation (see below). (5) Inhibition of ERK or TOR abolishes ALCAM-dependent translation; both kinases have been shown to be a pre-requisite for growth cone translation and are activated in growth cones by extracellular stimuli (Zhou and Snider, 2006;Jung and Holt, 2011).…”

Section: Discussionmentioning

confidence: 99%

Translation of the cell adhesion molecule ALCAM in axonal growth cones – regulation and functional importance

Thelen

Maier

Faber

et al. 2012

Journal of Cell Science

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Summary ALCAM is a cell adhesion molecule that is present on extending axons and has been shown to be crucial for elongation and navigation of retinal ganglion cell (RGC) axons. In the present study, we show that ALCAM mRNA is present in axonal growth cones of RGCs in vivo and in vitro, and that translation of ALCAM occurs in RGC growth cones separated from their soma. This growth cone translation is regulated by the 39-untranslated region (39-UTR) of ALCAM and depends on the activity of the kinases ERK and TOR (target of rapamycin). We also investigated the impact of the growth cone translation of ALCAM on axonal functions. Growth cone translation of ALCAM is crucial for the enhanced elongation of axons extending in contact with ALCAM protein. The local translation of ALCAM in the growth cone is able to rapidly counterbalance experimentally induced ALCAM internalization, thereby contributing to the maintenance of constant ALCAM levels in the plasma membrane. Assays where RGC axons have the choice to grow on laminin or both ALCAM and laminin -as is the case in the developing retina -reveal that the axonal preference for ALCAM-containing lanes depends on translation of ALCAM in growth cones. Taken together, these results show for the first time that translation of a cell adhesion molecule in growth cones, as well as the impact of this local translation on the behavior of axon and growth cone.

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“…Transfected cells were identified by GFP staining. The c-Jun fluorescent signals in transfected cells were quantified by calculating the mean pixels of the transfected cells on the unprocessed fluorescent images using the histogram function in Adobe Photoshop CS2 (20). To correct for background fluorescence, the pixel intensity of the same size area was measured immediately adjacent to the transfected cell, and this value was subtracted.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

D’Mello

2011

Journal of Biological Chemistry

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Histone deacetylase (HDAC) 7 is a member of the HDAC family of deacetylases. Although some of the HDAC proteins have been shown to regulate neuronal survival and death, whether HDAC7 has a similar role is not known. In this study, we show that HDAC7 protects neurons from apoptosis. In cerebellar granule neurons (CGNs) primed to undergo apoptosis by low potassium treatment, expression of HDAC7 protein is reduced. Reduced expression is also observed in CGNs induced to die by pharmacological inhibition of the proteasome, in cortical neurons treated with homocysteic acid, and in the striatum of R6/2 transgenic mice, a commonly used genetic model of Huntington disease. Forced expression of HDAC7 in cultured CGNs blocks low potassium-induced death, and shRNA-mediated suppression of its expression induces death in otherwise healthy neurons. HDAC7-mediated neuroprotection does not require its catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Moreover, pharmacological inhibitors of the PI3K-Akt or Raf-MEK-ERK signaling pathways or that of PKA, PKC, and Ca 2؉ /calmodulin-dependent protein kinase fail to reduce neuroprotection by HDAC7. We show that stimulation of c-jun expression, an essential feature of neuronal death, is prevented by HDAC7. shRNA-mediated suppression of HDAC7 expression leads to an increase in c-jun expression. Inhibition of c-jun expression by HDAC7 is mediated at the transcriptional level by its direct association with the c-jun gene promoter. Taken together, our results indicate that HDAC7 is a neuroprotective protein acting by a mechanism that is independent of its deacetylase activity but involving the inhibition of c-jun expression.Histone deacetylases (HDACs) 2 are the catalytic subunits of multiprotein complexes that deacetylate specific lysines in the tail residues of histones, resulting in the compaction of chromatin into a transcriptionally repressed state (reviewed in Refs. 1, 2). Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs regulate the acetylation status of a number of other non-histone proteins, suggesting complex functions of HDACs (1, 2). The 18 HDACs expressed in mammals have been grouped into four classes. Class I HDACs (HDAC1-3 and HDAC8) are composed primarily of a catalytic domain, expressed ubiquitously, and localize to the nucleus where they serve as transcriptional repressors. Class II HDACs (HDAC4 -7, HDAC9, and HDAC10) are larger proteins with an N-terminal regulatory domain involved in protein-protein interactions. These HDACs are expressed tissue-specifically and can shuttle between the nucleus and the cytoplasm in a phosphorylationdependent manner. HDAC11 is the sole member of the class IV HDAC subfamily. Members of the third class of deacetylases are called sirtuins (Sirt1-7). In contrast to proteins in the other three classes, which are zinc-dependent deacetylases, sirtuins are NAD-dependent enzymes.There is growing consensus that HDACs regulate neuronal survival and that deregulated...

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Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent β-Catenin mRNA Translation in Developing Hippocampal Neurons

Cited by 51 publications

References 53 publications

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Translation of the cell adhesion molecule ALCAM in axonal growth cones – regulation and functional importance

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

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