Tissue‐dependent variation in the expression of elongation factor‐1α isoforms: Isolation and characterisation of a cDNA encoding a novel variant of human elongation‐factor 1α

Knudsen, Sanne Møller; Frydenberg, Jane; Clark, Brian F. C.; Leffers, Henrik

doi:10.1111/j.1432-1033.1993.tb18064.x

Cited by 153 publications

(141 citation statements)

References 42 publications

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“…Expression of eEF1A2 is restricted to terminally differentiated cells of skeletal muscle, heart, and brain and dominates in the postnatal period (12). Loss of eEF1A2 expression because of mutation of the eEF1A2 gene in wasted (wst) mice results in progressive motor neuron degeneration, muscle atrophy, paralysis, and death within 30 days after birth (12)(13)(14). The neurodegenerative phenotype of wst mice is similar to that of Zpr1 Ϫ/ϩ mice (10) as well as mice with reduced expression of SMN (15,16).…”

mentioning

confidence: 71%

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

Mishra¹,

Gangwani²,

Davis

et al. 2007

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

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Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded ␤ helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1B␣ from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.growth factor receptor ͉ structure ͉ neurodegeneration ͉ spinal muscular atrophy ͉ cell cycle

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mentioning

confidence: 71%

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

Mishra¹,

Gangwani²,

Davis

et al. 2007

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

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“…In humans, two EEF1A protein isoforms (EEF1A1 and EEF1A2), which have similar elongation activity, are known (17,18). thus, we evaluated the effect of tIm knockdown on protein biosynthesis.…”

Section: Mechanisms Involved In Pro-proliferative and Anti-apoptotic mentioning

confidence: 99%

“…In humans, zation; atm, ataxia telangiectasia mutated; aKt, v-akt murine thymoma viral oncogene homolog; cDna, complementary Dna; cheK1, checkpoint kinase 1; cheK2, checkpoint kinase 2; chX, cycloheximide; csnK1e, casein kinase 1ε; ctrl, negative control; Dna, deoxyribonucleic acid; eeF1a2, eukaryotic elongation factor 1a2; fw, forward; hBV, hepatitis B virus; hcV, hepatitis c virus; hcc, hepatocellular carcinoma; IP, immunoprecipitation; mDm2, mouse double minute homolog 2; mDm4, mouse double minute homolog 4; mtoR, mammalian target of rapamycin; nl, normal liver; oF, oligofectamine control; p21, cyclin-dependent kinase inhibitor 1a (cDKn1a, cip1); p53, tumor protein p53; PI3K, phosphoinositide-3-kinase; Page, polyacrylamide gel electro phoresis; PeR1, period circadian clock 1; PeR2, period circadian clock 2; Pt, peritumorous, non-neoplastic liver tissue; PUma, Bcl2 binding component 3; qRt-PcR, quantitative real-time polymerase chain reaction; Rna, ribonucleic acid; RoRa, RaR-related orphan receptor a; rev, reverse; sDs, sodium dodecyl sulfate; sem, standard error of the mean; sinc, non-target control siRna; siRna, short interfering Rna; sitIm, siRna targeting timeless; tIm, timeless; tIPIn, tImeless interacting protein; tma, tissue microarray; WB, western immunoblotting two EEF1A isoforms are known. while EEF1A1 is expressed in almost all tissues, EEF1A2 expression was only reported in heart, brain and skeletal muscle (17,18). however, eeF1a2 exerts an anti-apoptotic function, which may explain its role in tumorigenesis (19).…”

Section: Introductionmentioning

confidence: 99%

Protumorigenic role of Timeless in hepatocellular carcinoma

Elgohary

Pellegrino

Neumann

et al. 2014

International Journal of Oncology

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Abstract. The mammalian timeless (TIM) protein interacts with proteins of the endogenous clock and essentially contributes to the circadian rhythm. In addition, TIM is involved in maintenance of chromosome integrity, growth control and development. Thus, we hypothesized that TIM may exert a potential protumorigenic function in human hepatocarcinogenesis. TIM was overexpressed in a subset of human HCCs both at the mRNA and the protein level. siRNA-mediated knockdown of TIM reduced cell viability due to the induction of apoptosis and G2 arrest. The latter was mediated via CHEK2 phosphorylation. In addition, siRNA-treated cells showed a significantly reduced migratory capacity and reduced expression levels of various proteins. Mechanistically, TIM directly interacts with the eukaryotic elongation factor 1A2 (EEF1A2), which binds to actin filaments to promote tumor cell migration. siRNA-mediated knockdown of TIM reduced EEF1A2 protein levels thereby affecting ribosomal protein biosynthesis. Thus, overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2. IntroductionMany biological processes show a circadian rhythm, which is controlled by an endogenous clock that synchronizes with day and night phases of the solar day. The periodical rhythm is generated by a molecular oscillator located in the suprachiasmatic nuclei of the hypothalamus, which controls peripheral oscillators in virtually any other cell (1). The circadian clock is organized through a complex network of transcriptiontranslational feedback loops that drive rhythmic expression patterns of core clock components in mammals (2).The Timeless (TIM) protein interacts with clock proteins and is essential for generation of a circadian rhythm in flies (3). In addition, phylogenetic sequence analysis revealed the presence of a paralogue in D. melanogaster (4), which is not involved in the core clock machinery, but is important for the maintenance of chromosome integrity, growth control, and development. In contrast, a single TIM gene has been identified in mammals, which acquired all of these functions as indicated by its role in DNA damage response, replication, and circadian rhythm (5-9). Consistently, TIM knockout resulted in embryonic lethality in mice (10). In addition, TIM and other clock genes have been linked to human carcinogenesis (11)(12)(13)(14). Using integrative molecular profiling we have recently identified that inactivation of Period homolog 3, a component of the clock machinery, occurs in human HCC indicating that dysregulation of this regulatory network may contribute to hepatocarcinogenesis (15).The eukaryotic elongation factor 1-α (EEF1A), a member of the G protein family, represents one of the four subunits that constitute the eukaryotic elongation factor 1 (16). In humans,

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“…eEF1A1 is expressed ubiquitously, whereas eEF1A2 expression is restricted to the heart, the brain, and the skeletal muscles in humans and rodents. 16,17 It has been shown that increased expression of eEF1A1 and eEF1A2 proteins is associated with increased cell proliferation, oncogenic transformation, and delayed cell senescence. 14,18,19 It is interesting to note that cellular redistribution of eEF1A is related to pH i .…”

mentioning

confidence: 99%

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

Kim

Namkung

Yoon

et al. 2009

Laboratory Investigation

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The formation of a pH gradient, which is characterized by intracellular alkalinization and extracellular acidification, plays a key role in the growth and metastasis of tumor cells. However, the underlying mechanisms of alkalinization-induced cell growth are not known. In this study, we investigated the roles of eukaryotic translation elongation factor 1 a (eEF1A) in alkalinization-induced cell growth. In all cell lines tested (NIH3T3, HEK293, and HeLa), cell growth was affected by the modulation of intracellular pH. In general, weak intracellular alkalinization produced increased cell growth, whereas intracellular acidification resulted in decreased cell growth. It is interesting to note that portions of actin-bound eEF1A proteins were gradually reduced from acidic to alkaline conditions, suggesting an increase in levels of functionally active, free-form eEF1A. Over-expression of eEF1A caused increased cell growth in HeLa cells. It should be noted that dissociation of eEF1A from actin by transfection with the actin-binding domain deleted eEF1A construct further increased cell growth under acidic conditions, whereas most of the intact eEF1A was bound to actin. Conversely, knockdown of eEF1A by treatment with eEF1A1 and eEF1A2 siRNAs nullified the effects of alkalinization-induced cell growth. The above findings suggest that an increase in free-form eEF1A under alkaline conditions plays a critical role in alkalinization-induced cell growth.

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Tissue‐dependent variation in the expression of elongation factor‐1α isoforms: Isolation and characterisation of a cDNA encoding a novel variant of human elongation‐factor 1α

Cited by 153 publications

References 42 publications

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

Protumorigenic role of Timeless in hepatocellular carcinoma

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

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