Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Shin, Chan Young; Kundel, Mitchell; Wells, David G.

doi:10.1523/jneurosci.2457-04.2004

Cited by 128 publications

(121 citation statements)

References 49 publications

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“…For example, CPEB1 regulates the expression of cyclin B1 in astrocytes, and blocking CPEB1 function prevents entrance into mitosis, leading to an inhibition of proliferation (6). Furthermore, we have shown in hippocampal neurons that tissue plasminogen activator (tPA), a serine protease that regulates the physiologic processes that necessitate tissue remodeling and cell migration, is regulated by CPEB1 (26). Along with b-catenin, MTDH, and cyclin B1, FABP7 is regulated by CPEB1 in astrocytes (27).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Kochanek

Wells

2013

Molecular Cancer Research

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“…Also of interest were changes in the tPA system, including t-PA and SERBP1. t-PA is an extracellular serine protease that is expressed after LTP induction and released after local mGluR-dependent synthesis (28,29). Proteolytic activity of t-PA is necessary for experience-dependent synaptic pruning, LTP consolidation, and the formation of perforated synaptic profiles (30).…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice

Liao¹,

Park²,

Xu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

161

150

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Fragile X syndrome (FXS) is a common inherited form of mental retardation that is caused, in the vast majority of cases, by the transcriptional silencing of a single gene, fmr1. The encoded protein, FMRP, regulates mRNA translation in neuronal dendrites, and it is thought that changes in translation-dependent forms of synaptic plasticity lead to many symptoms of FXS. However, little is known about the potentially extensive changes in synaptic protein content that accompany loss of FMRP. Here, we describe the development of a high-throughput quantitative proteomic method to identify differences in synaptic protein expression between wild-type and fmr1؊/؊ mouse cortical neurons. The method is based on stable isotope labeling by amino acids in cell culture (SILAC), which has been used to characterize differentially expressed proteins in dividing cells, but not in terminally differentiated cells because of reduced labeling efficiency. To address the issue of incomplete labeling, we developed a mathematical method to normalize protein ratios relative to a reference based on the labeling efficiency. Using this approach, in conjunction with multidimensional protein identification technology (MudPIT), we identified >100 proteins that are up-or down-regulated. These proteins fall into a variety of functional categories, including those regulating synaptic structure, neurotransmission, dendritic mRNA transport, and several proteins implicated in epilepsy and autism, two endophenotypes of FXS. These studies provide insights into the potential origins of synaptic abnormalities in FXS and a demonstration of a methodology that can be used to explore neuronal protein changes in neurological disorders. stable isotope labeling ͉ proteomics ͉ mass spectrometry ͉ fragile X syndrome F ragile X syndrome (FXS) is the most common inherited form of mental retardation. It is characterized by low IQ (1) and a broad set of symptoms other than retardation that compound the level of impairment. These include autistic spectrum behaviors, attention deficit and hyperactivity, childhood seizures, and several physical manifestations (2, 3). The most profound neuroanatomical abnormality seen in the brains of FXS patients is a preponderance of long, thin, and ''tortuous'' dendritic spines in cortex (4). This cortical phenotype is recapitulated in the fmr1 knockout (KO) mouse model, which also exhibits abnormal spine morphologies in the hippocampus and cerebellum (5, 6).In the vast majority of cases, FXS is caused by expansion of a trinucleotide repeat (CGG) within the 5Ј-untranslated region of the X-linked gene fmr1, resulting in its transcriptional silencing. The encoded protein, FMRP, can act as a translational suppressor of mRNAs in dendrites, controlling the localized, activity-dependent expression of a potentially large subset of synaptic proteins (7). Knocking out fmr1 in mouse results in a perturbation of various forms of translation-dependent synaptic plasticity, including some forms of long-term potentiation (LTP) and group I metabotropic...

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“…Of binding proteins known to mediate mRNA trafficking in dendrites, perhaps the best characterized is CPEB. CPEB facilitates mRNA targeting to dendrites (Huang et al, 2003) and triggers "on-site" translation in response to external signals (Shin et al, 2004).…”

Section: Export Of Mrnas To Neuronal Processesmentioning

confidence: 99%

RNA Trafficking and Local Protein Synthesis in Dendrites: An Overview

2006

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It is now widely accepted that mRNAs localize to dendrites and that translation of these mRNAs is regulated in response to neuronal activity. Recent studies have begun to reveal the underpinnings of these processes and to underscore the importance of local protein synthesis to synaptic remodeling and plasticity.When Steward and Levy (1982) first reported their observation of polyribosomes at the base of spines, the prevailing view was that all proteins were synthesized in the cell body and then transported to distal compartments of neurons. Steward and Levy's discovery, however, raised the intriguing possibility that mRNAs could be transported to synapses and locally translated in response to synaptic stimulation. This provided an elegant mechanism for spatially restricting gene expression within the neuron, such that individual synapses could independently regulate their morphology and efficacy, in a persistent, protein synthesis-dependent manner, in response to specific stimuli. It is now widely accepted that mRNAs do localize to dendrites and that translation of these mRNAs contributes to synaptic plasticity. As is evident from the collection of Mini-Reviews on dendritic protein synthesis in this issue of The Journal of Neuroscience, the field has evolved to focus on a series of key questions, including the following: (1) what mRNAs are present in dendrites? (2) How are these mRNAs transported from the nucleus into the dendrite? (3) How is translation of these mRNAs regulated by neuronal activity? and (4) What is the function of local translation of specific transcripts? In this brief introductory overview, we will consider each of these questions in turn.

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Rapid, Activity-Induced Increase in Tissue Plasminogen Activator Is Mediated by Metabotropic Glutamate Receptor-Dependent mRNA Translation

Cited by 128 publications

References 49 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

Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice

RNA Trafficking and Local Protein Synthesis in Dendrites: An Overview

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