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PubMed2004

Translational control by internal ribosome entry site in Saccharomyces cerevisiae.

To confirm the active involvement of the internal ribosome entry site (IRES)-dependent translation in living eukaryotes, Saccharomyces cerevisiae and HAP4 IRES were used for in vitro and in vivo experiments. Since HAP4 protein might be required for activating mRNAs transcription in yeast cells when they are released from catabolite repression, the translational efficiency of HAP4 mRNA is presumed to increase under such a condition. The in vitro experiment showed clearly that the translational mechanism was shifted from the cap-dependent to the completely IRES-dependent translation when the yeast cells were derepressed from catabolite repression. From in vivo experiment, it was confirmed that the IRES-dependent translational efficiency was in a low level at the beginning of the stationary growth phase, and was enhanced at the glucose-exhausted phase. These results indicate that yeast cells on the catabolite derepressed condition could get a large amount of HAP4 protein for the completely IRES-dependent translation, while the IRES-dependent translational efficiency is increased. It has been proven that IRES functions directing the initiation of translation in living yeast cells.

Gene Expression Regulation, Fungal↗

PubMed2004

The mTOR signaling pathway mediates control of ribosomal protein mRNA translation in rat liver.

Previous studies have shown that oral administration of leucine to fasted rats results in a preferential increase in liver in the translation of mRNAs containing an oligopyrimidine sequence at the 5'-end of the message (i.e. a TOP sequence). TOP mRNAs include those encoding the ribosomal proteins (rp) and translation elongation factors. In cells in culture, the preponderance of evidence suggests that translation of TOP mRNAs is regulated by the mammalian target of rapamycin (mTOR), a protein kinase that signals through ribosomal protein S6 kinase (S6K1) to rpS6. However, the results of previous studies were recently challenged by several reports suggesting that translation of TOP mRNAs is independent of mTOR, S6K1, and S6 phosphorylation. The purpose of the present study was to evaluate the role of mTOR in the stimulation of TOP mRNA translation by leucine in vivo. Fasted rats were treated with the mTOR inhibitor, rapamycin, prior to oral administration of leucine. It was found that rapamycin severely attenuated leucine-induced signaling through mTOR in liver. In addition, rapamycin prevented the enhanced translation of TOP mRNAs in rats administered leucine, as assessed by a decrease in the proportion of TOP mRNAs associated with polysomes (i.e. those mRNAs being actively translated). Instead, in rapamycin-treated rats, ribosomal protein mRNAs accumulated in the fraction containing monosomes (mRNA bound to one ribosome). The results suggest that in liver in vivo, mTOR-dependent signaling is critical for maximal stimulation of TOP mRNA translation.

Animals↗

PubMed2005

A new paradigm for translational control: inhibition via 5'-3' mRNA tethering by Bicoid and the eIF4E cognate 4EHP.

Translational control is a key genetic regulatory mechanism implicated in regulation of cell and organismal growth and early embryonic development. Initiation at the mRNA 5' cap structure recognition step is frequently targeted by translational control mechanisms. In the Drosophila embryo, cap-dependent translation of the uniformly distributed caudal (cad) mRNA is inhibited in the anterior by Bicoid (Bcd) to create an asymmetric distribution of Cad protein. Here, we show that d4EHP, an eIF4E-related cap binding protein, specifically interacts with Bcd to suppress cad translation. Translational inhibition depends on the Bcd binding region (BBR) present in the cad 3' untranslated region. Thus, simultaneous interactions of d4EHP with the cap structure and of Bcd with BBR renders cad mRNA translationally inactive. This example of cap-dependent translational control that is not mediated by canonical eIF4E defines a new paradigm for translational inhibition involving tethering of the mRNA 5' and 3' ends.

3' Untranslated Regions↗

PubMed2005

Translation of Sindbis virus 26S mRNA does not require intact eukariotic initiation factor 4G.

The infection of baby hamster kidney (BHK) cells by Sindbis virus gives rise to a drastic inhibition of cellular translation, while under these conditions the synthesis of viral structural proteins directed by the subgenomic 26S mRNA takes place efficiently. Here, the requirement for intact initiation factor eIF4G for the translation of this subgenomic mRNA has been examined. To this end, SV replicons that contain the protease of human immunodeficiency virus type 1 (HIV-1) or the poliovirus 2A(pro) replacing the sequences of SV glycoproteins have been constructed. BHK cells electroporated with the different RNAs synthesize protein C and the corresponding protease at late times. Notably, the proteolysis of eIF4G by both proteases has little effect on the translation of the 26S mRNA. In addition, recombinant viable SVs were engineered that encode HIV-1 PR or poliovirus 2A protease under the control of a duplicated late promoter. Viral protein synthesis at late times of infection by the recombinant viruses is slightly affected in BHK cells that contain proteolysed eIF4G. The translatability of SV genomic 49S mRNA was assayed in BHK cells infected with a recombinant virus that synthesizes luciferase and transfected with a replicon that expresses poliovirus 2Apro. Under conditions where eIF4G has been hydrolysed significantly the translation of genomic SV RNA was deeply inhibited. These findings indicate a different requirement for intact eIF4G in the translation of genomic and subgenomic SV mRNAs. Finally, the translation of the reporter gene that encodes green fluorescent protein, placed under the control of a second duplicate late promoter, is also resistant to the cleavage of eIF4G. In conclusion, despite the presence of a cap structure in the 5' end of the subgenomic SV mRNA, intact eIF4G is not necessary for its translation.

Animals↗

PubMed2004

Enhancement of IRES-mediated translation of the c-myc and BiP mRNAs by the poly(A) tail is independent of intact eIF4G and PABP.

The poly(A) tail at the 3' end of mRNAs enhances 5' cap-dependent translation initiation. We show that it also enhances IRES-directed translation of two cellular mRNAs in vitro and in vivo. The underlying mechanisms, however, differ fundamentally. In contrast to cap-dependent translation, IRES-driven translation continues to be enhanced by the poly(A) tail following proteolytic cleavage of eIF4G. Moreover, the poly(A) tail stimulates IRES-mediated translation even in the presence of PAIP2 or following effective depletion of the poly(A) binding protein (PABP) from HeLa cell extracts. The PABP-eIF4G bridging complex that is critical for cap-dependent translation is thus dispensable for the enhancement of the IRESs by the poly(A) tail. The polyadenylated mRNA translation from cellular IRESs is also profoundly sensitive to eIF4A activity in vitro. These mechanistic and molecular distinctions implicate the potential for a new layer of translational control mechanisms.

Antibodies, Monoclonal↗

PubMed2005

Ribosome stalling regulates IRES-mediated translation in eukaryotes, a parallel to prokaryotic attenuation.

It was previously shown that the mRNA for the cat-1 Arg/Lys transporter is translated from an internal ribosome entry site (IRES) that is regulated by cellular stress. Amino acid starvation stimulated cat-1 translation via a mechanism that requires translation of an ORF in the mRNA leader and remodeling of the leader to form an active IRES (the "zipper model" of translational control). It is shown here that slowing of the leader peptide elongation rate, either by cycloheximide or the introduction of rare codons, stimulated translation of the downstream ORF. These results suggest that ribosome stalling in the upstream ORF causes mRNA remodeling and formation of an active IRES. This control is reminiscent of translation attenuation in prokaryotic operons, where inhibition of translation elongation can regulate both mRNA translation and gene transcription by altering mRNA structure.

Amino Acid Sequence↗

PubMed2004

Femoro-tibial and menisco-tibial translation patterns in patients with unilateral anterior cruciate ligament deficiency--a potential cause of secondary meniscal tears.

OBJECTIVE: To analyze menisco-tibial and femoro-tibial translation patterns in healthy and ACL-deficient knees in different knee flexion angles under muscle activity. METHODS: The ACL-deficient and contralateral healthy knees of 10 patients were examined with an open MRI system at 30 degrees and 90 degrees of knee flexion, under isometric contraction of the extensors or flexor muscle groups. Translations between the tibia, the femoral condyles and the menisci were analyzed by three-dimensional image postprocessing. RESULTS: Posterior translation of the femur and menisci relative to the tibia occurred during knee flexion (30-90 degrees) in all knees. In ACL-deficient knees, posterior translation of the medial femoral condyle (+1.3 +/- 3.8 mm) was significantly larger than in healthy knee (-0.9 +/- 2.9 mm; p<0.05), while the translation pattern of the menisci was similar (med. meniscus 0.6 +/- 2.3 mm vs. 0.6 +/- 2.7 mm). Under isometric contraction of the extensors (relative to the flexor muscle group), an increased posterior position of the femur and menisci was observed at 30 degrees knee flexion, but not at 90 degrees. This applied to ACL-deficient and healthy knees. CONCLUSIONS: This study shows a significant increase of translation of the medial femoral condyle in ACL-deficient knees, whereas menisco-tibial translation remains almost unchanged. This difference in translation patterns indicates that the posterior horn of the medial meniscus might encounter shear, potentially explaining the high rate of secondary medial meniscal tears in patients with ACL-deficiency.

Adolescent↗

PubMed2006

The VPgPro protein of Turnip mosaic virus: in vitro inhibition of translation from a ribonuclease activity.

A role for viral encoded genome-linked (VPg) proteins in translation has often been suggested because of their covalent attachment to the 5' end of the viral RNA, reminiscent of the cap structure normally present on most eukaryotic mRNAs. We tested the effect of Turnip mosaic virus (TuMV) VPgPro on translation of reporter RNAs in in vitro translation systems. The presence of VPgPro in either wheat germ extract or rabbit reticulocyte lysate systems lead to inhibition of translation. The inhibition did not appear to be mediated by the interaction of VPg with the eIF(iso)4E translation initiation factor since a VPg mutant that does not interact with eIF(iso)4E still inhibited translation. Monitoring the fate of RNAs revealed that they were degraded as a result of addition of TuMV VPgPro or of Norwalk virus (NV) VPg protein. The RNA degradation was not the result of translation being arrested and was heat labile and partially EDTA sensitive. The capacity of TuMV VPgPro and of (NV) VPg to degrade RNA suggests that these proteins have a ribonucleolytic activity which may contribute to the host RNA translation shutoff associated with many virus infections.

Brassica↗

PubMed2000

Reinitiation of protein synthesis in Escherichia coli can be induced by mRNA cis-elements unrelated to canonical translation initiation signals.

In Eubacteria, de novo translation of some internal cistrons may be inefficient or impossible unless the 5' neighboring cistron is also translated (translational coupling). Translation reinitiation is an extreme case of translational coupling in which translation of a message depends entirely on the presence of a nearby terminating ribosome. In this work, the characteristics of mRNA cis-elements inducing the reinitiation process in Escherichia coli have been investigated using a combinatorial approach. A number of novel translational reinitiation sequences (TRSs) were thus identified, which show a wide range of reinitiation activities fully dependent on a translational coupling event and unrelated to the presence/absence of secondary structure or mRNA stability. Moreover, some of the isolated TRSs are similar to intercistronic sequences present in the E. coli genome.

5' Untranslated Regions↗

PubMed1994

Features in the 5' non-coding sequences of rabbit alpha and beta-globin mRNAs that affect translational efficiency.

The 5' non-coding sequence of rabbit beta-globin mRNA was mutagenized in an attempt to identify structural features that might contribute to the ability to support translation in an homologous rabbit reticulocyte lysate. Translational efficiency was not reduced by substitutions introduced in nearly every position of the beta-globin leader sequence, suggesting that the 5' non-coding domain of this highly efficient mRNA contains no special effector motifs. Instead, efficient translation appears to require only a moderately long leader sequence devoid of secondary structure, especially near the 5' end. Consistent with that interpretation, substitutions in several positions actually improved translation relative to the wild-type beta-globin leader sequence; experimental assessment of the secondary structure of these derivatives revealed a perfect inverse correlation between secondary structure content and translational efficiency. Other experiments probed the structural basis for the long-noted difference in translational efficiency between rabbit alpha and beta-globin mRNAs, a difference that was reproduced here using only the 5' non-coding domains of those mRNAs. The possibility that translation of ribosomal protein mRNAs might be modulated by a mechanism similar to that of alpha-globin mRNA is discussed. Because the beta-globin leader sequence has been incorporated into some popular expression vectors, and because globin genes are targets for gene therapy, this analysis of how globin mRNA leader sequences function in translation and how they can be improved may have practical applications.

Animals↗

PubMed1997

Artifacts in recording immediate mandibular translation: a laboratory investigation.

STATEMENT OF PROBLEM: Even though immediate mandibular translation has been extensively studied and analyzed, and its clinical significance emphasized, there is controversy as to whether it actually exists or whether it is just an artifact of the pantograph. PURPOSE: The aim of this study was to determine whether what appears to be pantographic evidence of immediate mandibular translation can actually be an artifact and, if so, to find a method to avoid it. MATERIAL AND METHODS: The first part of this article explains geometrically with computer vector graphics how pure rotation can produce a pantographic tracing on the horizontal plate that is identical to what would be seen for immediate mandibular translation. The second part of the article presents a technique that uses a modified pantograph that eliminates the rotational artifact and thus permits proper interpretation of true immediate mandibular translation. RESULTS: This study shows that pure rotation about the sagittal axis mimics immediate mandibular translation on a pantographic tracing when the plates are inferior to the transverse horizontal axis, produces scribings in an opposite direction for plates in a superior position, and produces no scribing when the plates are level with it. By modifying the pantograph so the tip of the scribing pin of the horizontal plate is level with the transverse horizontal axis, true immediate mandibular translation can most easily be differentiated from rotational artifact. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Rotation can cause artifacts that mimic immediate mandibular translation. A technique to avoid this problem is presented. This technique provides the foundation for a valid evaluation of patients to determine whether true immediate mandibular translation exists and whether it is clinically important.

Artifacts↗

PubMed2002

Transsaccadic perception of translating objects: effects of landmark objects and visual field position.

Previously Gysen, De Graef, and Verfaillie [Vision Research 42 (2002) 379] showed that, with stimulus displays presenting one stationary and one translating object, sensitivity for intrasaccadic displacements was higher for translating than for stationary objects. In the present paper the importance of the relative encoding of the path of the translating object towards the stationary object is investigated. In three experiments we compared detection of intrasaccadic displacements of translating objects in relative motion (moving towards the landmark object) and translating objects moving in isolation. No 'facilitatory' effect of relative motion was found. However a visual field effect was present. Performance was always better for the translating object presented in the lower part in comparison to the upper part of the visual field. A fourth experiment investigated the sensitivity for intrasaccadic displacements of stationary and translating objects presented in the upper as well as in the lower visual field. A lower visual field advantage was observed. The superior performance for translating objects, as was found previously, was confirmed in the lower and upper visual field.

Adult↗

PubMed2001

Translational control in vertebrate development.

Translational control plays a large role in vertebrate oocyte maturation and contributes to the induction of the germ layers. Translational regulation is also observed in the regulation of cell proliferation and differentiation. The features of an mRNA that mediate translational control are found both in the 5' and in the 3' untranslated regions (UTRs). In the 5' UTR, secondary structure, the binding of proteins, and the presence of upstream open reading frames can interfere with the association of initiation factors with the cap, or with scanning of the initiation complex. The 3' UTR can mediate translational activation by directing cytoplasmic polyadenylation and can confer translational repression by interference with the assembly of initiation complexes. Besides mRNA-specific translational control elements, the nonspecific RNA-binding proteins contribute to the modulation of translation in development. This review discusses examples of translational control and their relevance for developmental regulation.

Animals↗

PubMed2000

Efficient translation of mouse hypoxia-inducible factor-1alpha under normoxic and hypoxic conditions.

The heterodimeric hypoxia-inducible factor-1 (HIF-1), consisting of the subunits HIF-1alpha and HIF-1beta/ARNT, is a master transcriptional regulator of oxygen homeostasis. Under hypoxic conditions, HIF-1alpha levels very rapidly increase, mostly due to protein stabilization. However, translational regulation of HIF-1alpha has not been directly analyzed so far. Mouse HIF-1alpha exists as two mRNA isoforms (termed mHIF-1alphaI.1 and mHIF-1alphaI. 2) containing structurally different 5'-termini which might modulate translation initiation. Whereas the in vitro translation efficiency of these two mRNA isoforms was about equal, the mHIF-1alphaI.2 5'-untranslated region (5'-UTR) conferred significantly higher in vivo luciferase reporter gene activity than the mHIF-1alphaI.1 5'-UTR. Similar corresponding luciferase mRNA levels indicate translational rather than transcriptional alterations. Reporter gene expression was not affected upon exposure of transiently transfected cells to hypoxia (1% oxygen). Direct assessment of translational regulation by polysomal profile analysis of HeLaS3 cells showed that HIF-1alpha (and to a lower extent ARNT) mRNA was found mainly in the translationally active polyribosomal fractions under both normoxic and hypoxic conditions. In contrast, the association of mRNAs for beta-actin and ribosomal protein L28 with the polyribosomal fractions was substantially reduced under hypoxic conditions, suggesting decreased overall protein synthesis. Thus, efficient translation of mouse HIF-1alpha in a situation where the general translation efficiency is reduced represents a prerequisite for the very rapid accumulation of HIF-1alpha protein upon exposure to hypoxia.

Animals↗

PubMed2001

Cap-independent translation conferred by the 5'-untranslated region of human thymidine kinase mRNA.

Translational control is one of the mechanisms that regulate thymidine kinase (TK) expression in the cell cycle. Evidence for the TK mRNA sequence that is involved in its own translation has been lacking. In this report, we show that TK-deficient mouse fibroblasts transfected with pFLAG-TK express a TK mRNA containing the 5'-untranslated region (5'UTR) and produce two polypeptides, FLAG-TK and TK, resulting from an alternative initiation of translation. Most interestingly, the 5'UTR of TK allowed the translation of FLAG-TK mRNA to become cap-independent in an in vitro translation system. Furthermore, this 5'UTR sequence decreased significantly the efficiency of translation from the AUG codon of FLAG when the concentration of FLAG-TK RNA was low. Here, we also show that in normal human IMR-90 fibroblasts the induction of TK polypeptide by serum stimulation is insensitive to rapamycin treatment, which is known to inhibit the translations of transcripts of some growth-controlled genes by affecting the cap-binding efficiency. Taken together, we propose that the 5'UTR in TK mRNA might actually confer a secondary structure to regulate ribosome binding during translation in a cap-independent manner.

5' Untranslated Regions↗

PubMed2002

The relationship between clinical measurements of lower extremity posture and tibial translation.

OBJECTIVE: The purpose of this investigation was to determine if postures of the lower extremity were related to the amount of anterior tibial translation. DESIGN: Regression model of lower extremity postural measures used to predict the amount of tibial translation for a sample of convenience. BACKGROUND: Retrospective studies have indicated a link between certain lower extremity postures and prediction of anterior cruciate ligament injury status. What is not clear is whether these lower extremity postures cause, or occur as a result of anterior cruciate ligament injury. METHODS: Genu recurvatum, the thigh-foot angle, and navicular drop measures were obtained from the right leg of 43 uninjured college-aged subjects. Tibial translation was determined using a KT-1000 arthrometer. Gender related differences were determined with independent t-tests. Step-wise regression was performed to assess the relationship between postural measures and subject gender, and tibial translation. RESULTS: Very good to excellent inter- and intra-rater reliability was found for the postural measures. There was greater tibial translation (P=0.01) in females. The final regression model indicated a moderate relationship between sex of the subject, navicular drop and tibial translation (r=0.551). Genu recurvatum and thigh-foot angle were not significant predictors of tibial translation. CONCLUSIONS; We concluded that foot pronation has a greater impact on the amount of tibial translation than genu recurvatum and torsion of the lower leg in anterior cruciate intact subjects. RELEVANCE: Static clinical measures of lower extremity posture are commonly taken as predictors of outcome (both performance and injury). There may be little association between these static measures and dynamic performance.

Adult↗

PubMed1997

Measurements of vertebral translations using bone pins, surface markers and accelerometers.

OBJECTIVE: To compare invasive and non-invasive techniques for measuring the posterior-to-anterior translations of vertebrae during spinal manipulative therapy. DESIGN: This study represents a small part of a larger experiment. BACKGROUND: Despite the mechanical nature of spinal manipulative therapy, the mechanism by which it alleviates back pain is still unknown. An understanding of the deformation behaviour of the spine during spinal manipulative therapy would aid in the formulation of a hypothesis underlying its efficacy. METHODS: A clinician delivered posterior-to-anterior manipulative thrusts to the right transverse process of either T(10), T(11) or T(12) in two cadavers. Posterior-to-anterior translations of the bone pins and surface markers (embedded in and taped over T(10), T(11) and T(12), respectively) were recorded by cine cameras. Posterior-to-anterior accelerations, recorded by the accelerometers, were used to calculate posterior-to-anterior translations. Translation measurements made by using the surface markers and the accelerometers were compared to those made by using the bone pins. RESULTS: There were no significant differences between the posterior-to-anterior translations of vertebrae obtained from the surface markers, as compared to the bone pins. The accelerometers underestimated the absolute, and overestimated the relative, vertebral translations, respectively, compared to the bone pins. CONCLUSIONS: The translations measured by the surface markers were more similar to the translations derived from the bone pins than those calculated from the accelerometers. Three-dimensional surface marker arrays would therefore be more useful to determine all relative movements non-invasively.

Journal Article↗

PubMed2000

Cervical coupling during lateral head translations creates an S-configuration.

OBJECTIVE: To determine cervical coupling during the posture of lateral head translation relative to a fixed thoracic cage. DESIGN: Digitized measurements from anteroposterior cervical radiographs of 20 volunteers were obtained in neutral, left, and right lateral translation posture of the head compared to a fixed thorax. BACKGROUND DATA: Clinically, lateral translation of the head is a common posture. Ranges of motion and spinal coupling have not been reported for this movement. METHODS: Vertebral body corners, mid-lateral articular pillars and the superior spinous-lamina junction of C3-T4 were digitized on 60 radiographs. Using the orthogonal axis of positive x-direction to the left, vertical as positive y and anterior as positive z, digitized points were used to measure projected segmental z-axis rotation, y-axis rotation, and segmental lateral translations of each vertebra. RESULTS: Subjects translated their heads laterally a mean of 51 mm. The major coupled motion was lateral bending (z-axis rotation), which changed direction at the C4-C5 disc space creating an S-shape. Upper cervical (C3-C4) lateral bending was contralateral to the main motion of head translation direction. Lower cervical and upper thoracic lateral bending were ipsilateral. Other segmental motions averaged less than 1 mm and 1 degrees. CONCLUSIONS: Lateral head translations (x-axis) compared to a fixed thoracic cage can be large with a mean of 51 mm to one side. The major spinal coupling was lateral bending which changed direction at C4-C5 resulting in an S-configuration. This might have application in side impacts. All other segmental movements were small, less than 1 mm and 1 degrees. RELEVANCE: The clinically common posture of lateral head translation results in an S-shaped cervical spine and may occur in side impact trauma. This posture has not been studied for cervical coupling patterns or range of motion (ROM).

Adult↗