Evidence that fragile X mental retardation protein is a negative regulator of translation

Laggerbauer, Bernhard; Ostareck, Dirk H.; Keidel, Eva-Maria; Ostareck-Lederer, Antje; Fischer, Utz

doi:10.1093/hmg/10.4.329

Cited by 519 publications

(409 citation statements)

References 29 publications

(48 reference statements)

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“…U1A is able to homodimerize, even in mutants that have lost their capacity to interact with RNA; however, in the wildtype protein, homodimerization permits co-operative binding (Klein Gunnewiek et al, 2000). A mutant FMR1 (Fragile X mental retardation 1) I304N that is unable to oligomerize can still interact with RNA (Laggerbauer et al, 2001). In these three examples, RNA binding and oligomerization could be uncoupled, although oligomerization could reinforce binding.…”

Section: Discussionmentioning

confidence: 99%

Oligomerization of EDEN‐BP is required for specific mRNA deadenylation and binding

Cosson

Gautier-Courteille

Maniey

et al. 2006

Biology of the Cell

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Background information. mRNA deadenylation [shortening of the poly(A) tail] is often triggered by specific sequence elements present within mRNA 3 untranslated regions and generally causes rapid degradation of the mRNA. In vertebrates, many of these deadenylation elements are called AREs (AU-rich elements). The EDEN (embryo deadenylation element) sequence is a Xenopus class III ARE. EDEN acts by binding a specific factor, EDEN-BP (EDEN-binding protein), which in turn stimulates deadenylation.Results. We show here that EDEN-BP is able to oligomerize. A 27-amino-acid region of EDEN-BP was identified as a key domain for oligomerization. A mutant of EDEN-BP lacking this region was unable to oligomerize, and a peptide corresponding to this region competitively inhibited the oligomerization of full-length EDEN-BP. Impairing oligomerization by either of these two methods specifically abolished EDEN-dependent deadenylation. Furthermore, impairing oligomerization inhibited the binding of EDEN-BP to its target RNA, demonstrating a strong coupling between EDEN-BP oligomerization and RNA binding.Conclusions. These data, showing that the oligomerization of EDEN-BP is required for binding of the protein on its target RNA and for EDEN-dependent deadenylation in Xenopus embryos, will be important for the identification of cofactors required for the deadenylation process.

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Section: Discussionmentioning

confidence: 99%

Oligomerization of EDEN‐BP is required for specific mRNA deadenylation and binding

Cosson

Gautier-Courteille

Maniey

et al. 2006

Biology of the Cell

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“…The FMR1 knockout mouse exhibits deficits in neuronal pruning and alteration of FMRP-regulated protein synthesis (Comery, Harris et al 1997;Nimchinsky, Oberlander et al 2001). Since FMRP is thought to repress protein synthesis (Laggerbauer, Ostareck et al 2001;Li, Zhang et al 2001), a loss of function mutation of the FMR1 allele is expected to enhance protein synthesis of FMRPrepressed proteins. Consistent with this view, radiotracer autoradiography indicates enhanced protein expression in hypothalamus, thalamus, basolateral amygdala, hippocampus, frontal association, and posterior parietal cortex of FMR1 knockout mice (Qin, Kang et al 2005).…”

Section: Fragile X Mousementioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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“…Several in vitro studies have shown that pre-incubation of mRNAs with FMRP leads to translation inhibition [28,29]. However, this effect showed little or no specificity of mRNA sequence.…”

Section: Glossarymentioning

confidence: 99%

New insights into fragile X syndrome: from molecules to neurobehaviors

Jin

Warren

2003

Trends in Biochemical Sciences

189

124

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Fragile X syndrome -a common form of inherited mental retardation -is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP -RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.Fragile X syndrome is the most common form of inherited mental retardation, with the estimated prevalence of one in 4000 males and one in 8000 females. In addition to cognitive deficits, the phenotype of fragile X syndrome includes mildly abnormal facial features (a prominent jaw, high forehead and large ears), MACROORCHIDISM (see Glossary) in postpubescent males and subtle connective tissue abnormalities [1]. Many patients also manifest attention-deficit hyperactivity disorder and autistic-like behavior. As one of the first identified human disorders caused by trinucleotide repeat expansion, fragile X syndrome is the result of a massive CGG trinucleotide repeat expansion within the gene fragile X mental retardation 1 (FMR1). FMR1 is a highly conserved gene that consists of 17 exons, and spans , 38 kilobases (kb). Within the 4.4-kb FMR1 transcript, a CGG trinucleotide repeat is located in the 5 0 untranslated region (UTR) [2]. Among normal individuals, this CGG repeat is highly polymorphic in length and content, often punctuated by AGG interruptions. The normal repeat size ranges from 7 to , 54, with 30 repeats found in the most common allele. In most affected individuals, CGG repeats are massively expanded over 230 repeats (full mutation) and become abnormally hypermethylated, which results in the transcriptional silencing of FMR1 [1]. Identification of other mutations in FMR1 (e.g. deletions and a point mutation among patients with the typical phenotype, but without FRAGILE SITE expression) has confirmed that the FMR1 gene is the only gene involved in the pathogenesis of fragile X syndrome and the loss of FMR1 product -fragile X mental retardation protein (FMRP) -causes fragile X syndrome [1]. A mouse model of fragile X syndrome was created using gene targeting; the Fmr1-knockout mice exhibit macroorchidism and subtle deficits in learning and memory, which mimic the human phenotype [3].In this review, we discuss the recent progress in understanding the biological functions of FMRP and the physiological consequences of its absence that lead to mental retardation. Features of FMRPFMRP is widely expressed in fetal and adult tissues, with the most abundant expression in brain and testes [4]. FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consist...

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Evidence that fragile X mental retardation protein is a negative regulator of translation

Cited by 519 publications

References 29 publications

Oligomerization of EDEN‐BP is required for specific mRNA deadenylation and binding

Oligomerization of EDEN‐BP is required for specific mRNA deadenylation and binding

The cyclic AMP phenotype of fragile X and autism

New insights into fragile X syndrome: from molecules to neurobehaviors

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