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Results for “Translational repression”

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PubMed2006

Cap-dependent translational inhibition establishes two opposing morphogen gradients in Drosophila embryos.

In the early Drosophila embryo, asymmetric distribution of transcription factors, established as a consequence of translational control of their maternally derived mRNAs, initiates pattern formation . For instance, translation of the uniformly distributed maternal hunchback (hb) mRNA is inhibited at the posterior to form an anterior-to-posterior protein concentration gradient along the longitudinal axis . Inhibition of hb mRNA translation requires an mRNP complex (the NRE complex), which consists of Nanos (Nos), Pumilio (Pum), and Brain tumor (Brat) proteins, and the Nos responsive element (NRE) present in the 3' UTR of hb mRNA . The identity of the mRNA 5' effector protein that is responsible for this translational inhibition remained elusive. Here we show that d4EHP, a cap binding protein that represses caudal (cad) mRNA translation , also inhibits hb mRNA translation by interacting simultaneously with the mRNA 5' cap structure (m(7)GpppN, where N is any nucleotide) and Brat. Thus, by regulating Cad and Hb expression, d4EHP plays a key role in establishing anterior-posterior axis polarity in the Drosophila embryo.

Animals↗

PubMed1996

Engagement of tumor necrosis factor mRNA by an endotoxin-inducible cytoplasmic protein.

BACKGROUND: Tumor necrosis factor (TNF) production by macrophages plays an important role in the host response to infection. TNF-alpha gene expression in RAW 264.7 macrophages is predominantly regulated at the translational level. A key element in this regulation is an AU-rich (AUR) sequence located in the 3' untranslated region (UTR) of TNF mRNA. In unstimulated macrophages, the translation of TNF mRNA is inhibited via this AUR sequence. Upon stimulation with LPS, this repression is overcome and translation occurs. In this study, we attempted to identify cellular proteins that interact with the AUR sequence and thereby regulate TNF mRNA translation. MATERIALS AND METHODS: RNA probes corresponding to portions of TNF mRNA 3' UTR were synthesized. These labeled RNAs were incubated with cytoplasmic extracts of either unstimulated or lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages. The RNA/protein complexes formed were analyzed by gel retardation. Ultraviolet (UV) cross-linking experiments were performed to determine the molecular weight of the proteins involved in the complexes. RESULTS: TNF mRNA AUR sequence formed two complexes (1 and 2) of distinct electrophoretic mobilities. While the formation of complex 1 was independent of the activation state of the macrophages from which the extracts were obtained, complex 2 was detected only using cytoplasmic extracts from LPS-stimulated macrophages. Upon UV cross-linking, two proteins, of 50 and 80 kD, respectively, were capable of binding the UAR sequence. The 50-kD protein is likely to be part of the LPS-inducible complex 2, since its binding ability was enhanced upon LPS stimulation. Interestingly, complex 2 formation was also triggered by Sendaï virus infection, another potent activator of TNF mRNA translation in RAW 264.7 macrophages. In contrast, complex 2 was not detected with cytoplasmic extracts obtained from B and T cell lines which are unable to produce TNF in response to LPS. Protein tyrosine phosphorylation is required for LPS-induced TNF mRNA translation. Remarkably, the protein tyrosine phosphorylation inhibitor herbimycin A abolished LPS-induced complex 2 formation. Complex 2 was already detectable after 0.5 hr of LPS treatment and was triggered by a minimal LPS dose of 10 pg/ml. CONCLUSIONS: The tight correlation between TNF production and the formation of an LPS-inducible cytoplasmic complex suggests that this complex plays a role in the translational regulation of TNF mRNA.

Animals↗

PubMed2004

Translational regulation of Hsp90 mRNA. AUG-proximal 5'-untranslated region elements essential for preferential heat shock translation.

Heat shock in Drosophila results in repression of most normal (non-heat shock) mRNA translation and the preferential translation of the heat shock mRNAs. The sequence elements that confer preferential translation have been localized to the 5'-untranslated region (5'-UTR) for Hsp22 and Hsp70 mRNAs (in Drosophila). Hsp90 mRNA is unique among the heat shock mRNAs in having extensive secondary structure in its 5'-UTR and being abundantly represented in the non-heat shocked cell. In this study, we show that Hsp90 mRNA translation is inefficient at normal growth temperature, and substantially activated by heat shock. Its preferential translation is not based on an IRES-mediated translation pathway, because overexpression of eIF4E-BP inhibits its translation (and the translation of Hsp70 mRNA). The ability of Hsp90 mRNA to be preferentially translated is conferred by its 5'-UTR, but, in contrast to Hsp22 and -70, is primarily influenced by nucleotides close to the AUG initiation codon. We present a model to account for Hsp90 mRNA translation, incorporating results indicating that heat shock inhibits eIF4F activity, and that Hsp90 mRNA translation is sensitive to eIF4F inactivation.

5' Untranslated Regions↗

PubMed1974

Rapid loss of translatable messenger RNA of phosphoenolpyruvate carboxykinase during glucose repression in liver.

The rate of synthesis of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) in rat liver decreased with a half-life of 30 min after fasted rats were refed either a chow diet or glucose. A requirement for both glucose and insulin to bring about this rapid deinduction was shown, as well as the ability of dibutyryl adenosine 3':5'-cyclic monophosphate to block the decrease in enzyme synthesis. Estimates of the stability of messenger RNA of phosphoenolpyruvate carboxykinase were made by using the inhibitors actinomycin D and cordycepin to block further messenger RNA synthesis, and then measuring the decrease in specific enzyme synthesis. It is suggested that the use of actinomycin D yields an overestimation of the template stability. The results with cordycepin imply that the enzyme messenger RNA has a short half-life of approximately 1 hr. Thus, it is possible that deinduction may proceed by way of a decrease in messenger RNA production, leading to a rapid fall in the synthesis of phosphoenolpyruvate carboxykinase.

Animals↗

PubMed2003

Role of cysteine amino acid residues on the RNA binding activity of human thymidylate synthase.

The role of cysteine sulfhydryl residues on the RNA binding activity of human thymidylate synthase (TS) was investigated by mutating each cysteine residue on human TS to a corresponding alanine residue. Enzymatic activities of TS:C43A and TS:C210A mutant proteins were nearly identical to wild-type TS, while TS:C180A and TS:C199A mutants expressed >80% of wild-type enzyme activity. In contrast, TS:C195A was completely inactive. Mutant proteins, TS:C195A, TS:C199A and TS:C210A, retained RNA binding activity to nearly the same degree as wild-type human TS. RNA binding activity of TS:C43A was reduced by 30% when compared to wild-type TS, while TS:C180A was completely devoid of RNA binding activity. In vitro translation studies confirmed that mutant proteins TS:C43A, TS:C195A, TS:C199A and TS:C210A, significantly repressed human TS mRNA translation, while TS:C180A was unable to do so. To confirm the in vivo significance of the cysteine sulfhydryl residue, mutant proteins TS:C180A and TS:C195A were each expressed in human colon cancer HCT-C18:TS(-) cells that expressed a functionally inactive TS. A recombinant luciferase reporter gene under the control of a TS-response element was co-transfected into these same cells, and luciferase activity increased in the presence of the TS:C195A mutant TS protein to a level similar to that observed upon expression of wild-type TS protein. In contrast, luciferase activity remained unchanged in cells expressing the TS:C180A mutant protein. Taken together, these findings identify Cys-180 as a critical residue for the in vitro and in vivo translational regulatory effects of human TS.

Alanine↗

PubMed1997

Vitamin B12 repression of the btuB gene in Salmonella typhimurium is mediated via a translational control which requires leader and coding sequences.

Expression of the Salmonella typhimurium btuB gene, which encodes an outer membrane protein required for vitamin B12 uptake, is repressed by the presence of external vitamin B12. We have, by means of a mutational analysis, investigated which btuB sequences are required for repression. Analysis of btuB::lacZ transcriptional and translational fusions of various lengths showed that the control was exerted mainly at the translational level and required both coding and leader sequences in the btuB transcript. Regulatory mutants with a B12 non-repressible phenotype were isolated and the mutations were shown to be located at several sites within the btuB leader. Analysis of constructs carrying site-directed point mutations, which either destabilized or restabilized a putative RNA hairpin that sequesters the btuB ribosomal binding site, demonstrated that this hairpin was essential for normal repression. Comparison of the S. typhimurium btuB gene with the previously characterized S. typhimurium cbiA and Escherichia coli btuB genes reveals significant similarities as well as differences in the cis-acting sequences required for repression.

Bacterial Outer Membrane Proteins↗

PubMed2005

Repression of light signaling by Arabidopsis SPA1 involves post-translational regulation of HFR1 protein accumulation.

Arabidopsis uses two major classes of photoreceptors to mediate seedling de-etiolation. The cryptochromes (cry1 and cry2) absorb blue/ultraviolet-A light, whereas the phytochromes (phyA-phyE) predominantly regulate responses to red/far-red light. Arabidopsis COP1 represses light signaling by acting as an E3 ubiquitin ligase in the nucleus, and is responsible for targeted degradation of a number of photomorphogenesis-promoting factors, including HY5, LAF1, phyA, and HFR1. Distinct light signaling pathways initiated by multiple photoreceptors (including both phytochromes and cryptochromes) eventually converge on COP1, causing its inactivation and nuclear depletion. Arabidopsis SPA1, which encodes a protein structurally related to COP1, also represses light signaling under various light conditions. In this study, we present genetic evidence supporting that HFR1, which encodes a photomorphogenesis-promoting bHLH transcription factor, acts downstream of SPA1 and is required for different subsets of branch pathways of light signaling controlled by SPA1 under different light conditions. We show that SPA1 physically interacts with HFR1 in a yeast two-hybrid assay and an in vitro co-immunoprecipitation assay. We demonstrate that higher levels of HFR1 protein accumulate in the spa1 mutant background under various light conditions, including far-red, red, blue, and white light, whereas a marginal increase in HFR1 transcript level is only seen in dark- and far-red light-grown spa1-100 mutants. Together, our data suggest that repression of light signaling by Arabidopsis SPA1 likely involves post-translational regulation of HFR1 protein accumulation.

Arabidopsis↗

PubMed1998

Transcriptional and translational regulation of major heat shock proteins and patterns of trehalose mobilization during hyperthermic recovery in repressed and derepressed Saccharomyces cerevisiae.

Patterns of heat shock gene transcription and translation, as well as trehalose content, were investigated in both glucose (repressed) and acetate (derepressed) grown cells of Saccharomyces cerevisiae during heat shock and subsequent return of cells to 25 degrees C. Heat-shocked cells (37 degrees C for 30 min), grown in either glucose- or acetate-supplemented media, initially acquired high thermotolerance to a 50 degrees C heat stress, which was progressively lost when cultures were allowed to recover at 25 degrees C and subsequently exposed to a second heat stress. In all cases, with the notable exception of repressed cells of a relatively thermosensitive strain, inhibition of protein synthesis and coincident decrease in trehalose accumulation during the heat shock had little effect on the kinetics of loss of thermotolerance. Heat shock at 37 degrees C elicited a marked increase in transcription and translation of genes encoding major heat shock proteins (hsps). During recovery at 25 degrees C, both metabolic activities were suppressed followed by a gradual increase in hsp mRNA transcription to levels observed prior to heat shock. De novo translation of hsp mRNAs, however, was no longer observed during the recovery phase, although immunodetection analyses demonstrated persistence of high levels of hsps 104, 90, 70, and 60 in cells throughout the 240-min recovery period. In addition, while heat shock induced trehalose was rapidly degraded during recovery in repressed cells, levels remained high in derepressed cells. Results therefore indicated that the progressive loss of induced thermotolerance exhibited by glucose- and acetate-grown cells was not closely correlated with levels of hsp or trehalose. It was concluded that both constitutive and de novo synthesized hsps require heat shock associated activation to confer thermotolerance and this modification is progressively reversed upon release from the heat-shocked state.

Acetates↗

PubMed1996

Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line.

Recent studies have indicated that nitric oxide may affect iron metabolism through disruption of the iron-sulfur complex of iron regulatory protein-1, a translational regulator. In the present study, we report that heterologous expression of murine macrophage nitric oxide synthase (NOS-2) in the human erythroleukemic K562 cell line results in constitutive production of nitric oxide associated with inhibition of hemoglobin expression. K562 cells were transfected with an episomally-maintained, hygromycin-selectable expression vector bearing the coding region of NOS-2. Constitutive NOS expression was detected by Western blotting of cell lysates and by the accumulation of nitrite in the culture media. Although NOS-transfected cells grew more slowly than control cells, they were able to maintain constitutive expression of NOS and production of nitric oxide for more than 1 month following transfection. The hemoglobin content of NOS-transfected K562 cells was less than one-fifth that of control cells, but increased markedly if NOS inhibitor was included in the culture media. The nitric oxide-mediated inhibition of hemoglobin expression was reversed by supplementing the culture media with 20 mumol/L hemin or 0.5 mmol/L 5-amino-levulinate, indicating that nitric oxide did not directly inhibit hemoglobin synthesis, but likely acted on a step in heme synthesis. mRNA levels for globin and erythroid aminolevulinic acid synthase (eALAS) were the same in both NOS-transfected and control cells. Our observations indicate that hemoglobin expression is inhibited by nitric oxide in NOS-transfected K562 cells by posttranscriptional repression of eALAS, the first enzyme of the heme biosynthetic pathway. The most likely mechanism is a nitric oxide-mediated translational repression of eALAS, as was recently demonstrated for ferritin synthesis. These observations further illustrate the potential for endogenously produced nitric oxide to regulate cellular posttranscriptional events. In particular, our observations may be relevant to the role of nitric oxide in anemia and lowered blood hemoglobin concentrations that are associated with chronic infections, such as tuberculosis or parasitic disease.

5-Aminolevulinate Synthetase↗

PubMed1968

Catabolite repression in Escherichia coli. A study of two hypotheses.

1. Two hypotheses to account for general catabolite repression of the lactose enzymes in Escherichia coli were tested: the dilution model of Palmer & Moses (1967), and the specific catabolite repressor model of Loomis & Magasanik (1965, 1967). 2. The dilution model predicts that in mutants lacking the i-o regulation system the differential rate of beta-galactosidase synthesis should increase when amino acid-synthesizing enzymes are repressed by the presence of amino acids in the medium. It also predicts that with such mutants the total absence of P(i) from the medium should not result in the complete cessation of beta-galactosidase synthesis that is observed with wild-type cells. 3. Neither prediction was confirmed experimentally, and it is concluded that this model cannot explain catabolite repression. 4. The specific repressor hypothesis depends on the properties of a strain of E. coli carrying the CR(-) mutation. It requires both that cells of this genotype should be totally resistant to general catabolite repression and that this resistance should be specific for the lactose enzymes. 5. In fact the synthesis of beta-galactosidase by CR(-) cells, though showing resistance to catabolite repression by growth on glucose, was found to be repressed in several other circumstances. 6. Two other inducible enzymes, l-tryptophanase and d-serine deaminase, also showed resistance to repression by glucose in CR(-) cells. 7. It is concluded that this model, too, does not account for general catabolite repression. 8. Strains carrying deletions at either end of the lactose operon that extend into the structural genes of the operon continue to exhibit catabolite repression. 9. These experiments appear to eliminate the possibility that catabolite repression operates at the level of DNA transcription, and suggest that repression affects instead the translation of messenger RNA into protein.

Caseins↗

PubMed2003

Translational control of maternal glp-1 mRNA by POS-1 and its interacting protein SPN-4 in Caenorhabditis elegans.

The translation of maternal glp-1 mRNAs is regulated temporally and spatially in C. elegans embryos. The 3' UTR (untranslated region) of the maternal glp-1 mRNA is important for both kinds of regulation. The spatial control region is required to suppress translation in the posterior blastomeres. The temporal one is required to suppress translation in oocytes and one-cell stage embryos. We show that a CCCH zinc-finger protein, POS-1, represses glp-1 mRNA translation by binding to the spatial control region. We identified an RNP-type RNA-binding protein, SPN-4, as a POS-1-interacting protein. SPN-4 is present developmentally from the oocyte to the early embryo and its distribution overlaps with that of POS-1 in the cytoplasm and P granules of the posterior blastomeres. SPN-4 binds to a subregion of the temporal control region in the 3' UTR and is required for the translation of glp-1 mRNA in the anterior blastomeres. We propose that the balance between POS-1 and SPN-4 controls the translation of maternal glp-1 mRNA.

3' Untranslated Regions↗

PubMed1993

The IRE (iron regulatory element) family: structures which regulate mRNA translation or stability.

Iron regulatory elements (IREs) are a family of 28 nucleotide, non-coding elements which regulate the translation of ferritin mRNA (iron storage), erythroid delta-aminolevulinic acid synthase mRNA (heme synthesis) and the stability of the transferrin receptor (TfR) mRNA (iron uptake). IREs in the 5' end control translation (ribosome binding) and IREs in the 3' end control turnover (degradation). The specific regulator protein, the IRE-BP, is a member of the aconitase family but binds RNA only in the apo form without the Fe-S cluster. Cellular iron alters the IRE/IRE-BP interaction leading to translation of ferritin and eALAS mRNAs but degradation of the TfR mRNA. IRE function requires proximity to the 5' cap, achieved either by a short leader (eALAS) or a long, base-pairing flanking region (FL) (ferritin); a conserved triplet of FL base pairs enhances repression of ferritin mRNA. TfR mRNA has five AU-rich IREs which can also form an alternate structure with inter-IRE base pairs, in the absence of the IRE-BP. Ferritin IREs regulate both translation repression (negative control-IRE-BP dependent) and enhancement (positive control-initiation factor dependent); IRE-BP binding induces conformational changes in the FL. IREs use CAGUGU/C to form a hairpin loop with specific variations in the stem such as internal or bulge loops. A current structural model obtained using metallonucleases (1,10-phenanthroline-Cu, Fe-EDTA, Fe-bleomycin) and a preliminary analysis of the NMR spectrum, is a distorted helix with folds. The effect of cellular iron, Fe-S clusters and heme on the IRE-BP/RNA is not completely understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Regulation of ferritin mRNA translation in primary erythroblasts: exogenous c-Kit plus EpoR signaling mimics v-ErbA oncoprotein activity.

In general, translation efficiency of ferritin mRNAs is modulated by variations in iron supply. In primary avian erythroblasts undergoing short-term proliferation, however, ferritin heavy chain (ferH) mRNA is repressed at all iron levels. Yet, expression of v-ErbA oncoprotein is sufficient to reinduce ferH mRNA utilization at physiological iron concentrations. Since overexpression of the receptor tyrosine kinase c-Kit and erythropoietin receptor (EpoR) stimulates long-term proliferation of primary erythroblasts like v-ErbA, we analyzed the impact of cooperation between c-Kit and EpoR on the regulation of iron storage. Whereas endogenous c-Kit in combination with exogenous EpoR had no significant effect, ectopic overexpression of both receptors abolished translational repression of ferH mRNA upon iron administration. Thus, high-intensity signaling through c-Kit plus EpoR pathways mimics the v-ErbA-mediated regulatory phenotype.

Animals↗

PubMed1986

Transcriptional-translational regulation of muscle-specific protein synthesis and its relationship to chondrogenic stimuli.

Demineralized bone (bone matrix) has a well-characterized ability to evoke the re-differentiation of cells derived from skeletal muscle into chondrocytes. Recent investigations in this laboratory have shown that muscle-specific (alpha) actin synthesis continues throughout redifferentiation. Conversely, expression of the cartilage phenotype is associated with repression of muscle-specific enzyme synthesis. The present experiments were undertaken to determine the mode of genomic regulation responsible for control of these muscle-specific syntheses. As part of these experiments, we investigated the ability of embryonic and adult RNA to direct translation in vitro. The results indicate that unfractionated (total) RNA is capable of directing the efficient synthesis of actin, but not myosin heavy or light chains. Decreased abundance of polyadenylated mRNA cannot account for lack of myosin synthesis. Polyadenylated mRNA, however, directed synthesis of actin and myosin with an efficiency greater than that of total RNA. This data suggested that embryonic total RNA was subject to translational control. Dot blot hybridization against cDNA probes for alpha-actin, myosin heavy chain, and fast light chains demonstrated that myogenic cells were subject to a pattern of mixed transcriptional and translational control. It is hypothesized that full expression of the muscle phenotype involves sequential release of transcriptional, and subsequently, the translational controls. We have also observed that cultures of skeletal muscle on bone matrix contain mRNA for muscle-specific proteins, even through the period normally characterized by chondrogenesis. In the absence of concurrent enzyme protein synthesis, it appears that one action of bone matrix is to continue genomic controls that in the source skeletal muscle maintain the genome in an embryonic (translationally repressed) state.

Animals↗

PubMed1992

Cobalamin (vitamin B12) repression of the Cob operon in Salmonella typhimurium requires sequences within the leader and the first translated open reading frame.

Expression of the Cob operon in Salmonella typhimurium is repressed by cobalamin (Cbl). Here it is shown that Cbl repression is mediated by a post-transcriptional regulatory mechanism that requires sequences within the leader and the first translated open reading frame, the cbiA gene. Transcriptional and translational Cob::lacZ fusions containing various lengths of Cob DNA were analysed. In a translational Cob::lacZ fusion 407 bp of leader sequence (+69 to +476) was sufficient to confer normal repression. However in a transcriptional Cob::lacZ fusion a 618 bp region (+69 to +687) was required for normal repression. This 618 bp region included sequences in the leader as well as sequences within the cbiA gene. Point mutations which resulted in loss of repression control were isolated and shown to be clustered in the leader sequence (+257 to +380). This region contains a putative hairpin-loop structure which we propose functions as an RNA operator site for a vitamin B12-responsive repressor protein.

Base Sequence↗

PubMed1989

Arginine restriction induced by delta-N-(phosphonacetyl)-L-ornithine signals increased expression of HIS3, TRP5, CPA1, and CPA2 in Saccharomyces cerevisiae.

delta-N-(Phosphonacetyl)-L-ornithine (PALO), a transition state analog inhibitor of ornithine transcarbamylase, induced arginine limitation in vivo in Saccharomyces cerevisiae. Arginine restriction caused increased expression of HIS3 and TRP5, measured by the beta-galactosidase activity in strains carrying chromosomally integrated fusions of the promoter regions of each gene with the lacZ gene of Escherichia coli. The increase in beta-galactosidase activity induced by PALO was reversed by the addition of arginine and was dependent on GCN4 protein. These results indicate that PALO, like 3-amino-1,2,4-triazole DL-5-methyltryptophan, can be used to study the effect of limitation of a single amino acid, arginine, on the expression of genes under the general amino acid control regulatory system. Arginine deprivation imposed by PALO also caused increased expression of CPA1 and CPA2, coding respectively for the small and large subunits of arginine-specific carbamyl-phosphate synthetase. The observed increase was GCN4 dependent and was genetically separable from arginine-specific repression of CPA1 mRNA translation. The 5'-flanking regions of CPA1 (reported previously) and CPA2 determined in this study each contained at least two copies of the sequence TGACTC, shown to bind GCN4 protein. The beta-galactosidase activities expressed from CPA1- and CPA2-lacZ fusions integrated into the nuclear DNA of gcn4 mutant strains were five to six times less than in the wild type, when both strains were grown under depressed conditions. The gcn4 mutation reduced basal expression of both CPA1 and CPA2. The addition of arginine to strains containing the CPA1-lacZ fusion further reduced beta-galactosidase activity of the gcn4 mutant, indicating independent regulation of the CPA1 gene by the general amino acid control and by arginine-specific repression. In strains overproducing GCN4 protein, the translational control completely overrode transcriptional activation of CPA1 by general amino acid control.

Amino Acids↗

PubMed2001

Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1.

All nuclear-encoded mRNAs contain a 5' cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles.

Fragile X syndrome is caused by the absence of the fragile X mental retardation protein (FMRP). This RNA-binding protein is widely expressed in human and mouse tissues, and it is particularly abundant in the brain because of its high expression in neurons, where it localizes in the cell body and in granules throughout dendrites. Although FMRP is thought to regulate trafficking of repressed mRNA complexes and to influence local protein synthesis in synapses, it is not known whether it has additional functions in the control of translation in the cell body. Here, we have used recently developed approaches to investigate whether FMRP is associated with the translation apparatus. We demonstrate that, in the brain, FMRP is present in actively translating polyribosomes, and we show that this association is acutely sensitive to the type of detergent required to release polyribosomes from membranous structures. In addition, proteomic analyses of purified brain polyribosomes reveal the presence of several RNA-binding proteins that, similarly to FMRP, have been previously localized in neuronal granules. Our findings highlight the complex roles of FMRP both in actively translating polyribosomes and in repressed trafficking ribonucleoparticle granules.

Animals↗