Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Ruest, L. Bruno; Marcotte, Richard; Wang, Eugenia

doi:10.1074/jbc.m110685200

Cited by 122 publications

(118 citation statements)

References 35 publications

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“…This may provide a mechanism by which muscarinic activation can increase dendritic translation and may also allow for muscarinic regulation of other functions of eEF1A2. eEF1A has been demonstrated to bind and bundle actin (49), bind microtubules (50,51), bind calmodulin (52), and regulate apoptosis (53). Also, this interaction may provide a molecular mechanism underlying functional differences between the two closely related mAChR subtypes, M 2 and M 4 .…”

Section: Discussionmentioning

confidence: 99%

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

McClatchy¹,

Knudsen²,

Clark³

et al. 2002

Journal of Biological Chemistry

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The activation of the muscarinic acetylcholine receptor (mAChR) family, consisting of five subtypes (M 1 -M 5 ), produces a variety of physiological effects throughout the central nervous system. However, the role of each individual subtype remains poorly understood. To further elucidate signal transduction pathways for specific subtypes, we used the most divergent portion of the subtypes, the intracellular third (i3) loop, as bait to identify interacting proteins. Using a brain pull-down assay, we identify elongation factor 1A2 (eEF1A2) as a specific binding partner to the i3 loop of M 4 , and not to M 1 or M 2 .In addition, we demonstrate a direct interaction between these proteins. In the rat striatum, the M 4 mAChR colocalizes with eEF1A2 in the soma and neuropil. In PC12 cells, endogenous eEF1A2 co-immunoprecipitates with the endogenous M 4 mAChR, but not with the endogenous M 1 mAChR. In our in vitro model, M 4 dramatically accelerates nucleotide exchange of eEF1A2, a GTP-binding protein. This indicates the M 4 mAChR is a guanine exchange factor for eEF1A2. eEF1A2 is an essential GTP-binding protein for protein synthesis. Thus, our data suggest a novel role for M 4 in the regulation of protein synthesis through its interaction with eEF1A2.In the central nervous system, the muscarinic acetylcholine receptors (mAChR) 1 play crucial roles in learning, memory, movement, analgesia, and sleep (1-3). Dysfunction in mAChR signaling has been implicated in brain disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia (4 -6). The mAChRs belong to the G-protein-coupled receptor (GPCR) superfamily. Upon agonist binding, GPCRs bind and activate heterotrimeric G-proteins, which in turn activate various downstream targets. There are two distinct, well characterized G-protein signaling pathways activated by the five mAChR subtypes. M 1 , M 3 , and M 5 couple to G q , which stimulates phospholipase C-␤, and thus releases calcium from intracellular stores and activates protein kinase C (7, 8). M 2 and M 4 are coupled to G i/o , which regulates adenylate cyclase (9). These subtypes are expressed throughout the brain, and, in some brain regions, multiple subtypes are expressed in individual neurons (10). The diversity of physiological effects and the overlapping expression pattern of the muscarinic receptor subtypes suggest that there are signaling pathways initiated by the mAChRs independent of these two heterotrimeric G-protein pathways.Signaling pathways independent of heterotrimeric G-proteins have been reported throughout the GPCR superfamily (11-14). Evidence supporting this hypothesis stems from the identification of novel binding partners of GPCRs other than the traditional heterotrimeric G-proteins. Within the muscarinic family in particular, there is an especially large body of evidence to suggest the existence of nontraditional signaling pathways. There are many reports of G-protein-independent regulation of ion channels by mAChRs (15-18). Moreover, the M 3 mAChR has been found to associate ...

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Section: Discussionmentioning

confidence: 99%

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

McClatchy¹,

Knudsen²,

Clark³

et al. 2002

Journal of Biological Chemistry

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“…It is also possible, however, that the two eEF1A isoforms have subtly (or even substantially) different noncanonical roles. Certainly, it has been demonstrated in myoblasts that while eEF1A1 is pro-apoptotic (Ruest et al, 2002), eEF1A2 is anti-apoptotic. Moreover, it has recently been shown that co-expression of eEF1A2 and peroxiredoxin, Prdx1, renders NIH3T3 cells dramatically resistant to apoptotic death induced by exposure to oxidative stress (Chang and Wang, 2006).…”

Section: Discussionmentioning

confidence: 99%

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

et al. 2007

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The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-a) making analysis with commercial antibodies difficult. We wanted to establish the expression pattern of eEF1A2 in ovarian cancer of defined histological subtypes at both the RNA and protein level, and to establish the mechanism for the overexpression of eEF1A2 in tumours. We show that while overexpression of eEF1A2 is seen at both the RNA and protein level in up to 75% of clear cell carcinomas, it occurs at a lower frequency in other histological subtypes. The copy number at the EEF1A2 locus does not correlate with expression level of the gene, no functional mutations were found, and the gene is unmethylated in both normal and tumour DNA, showing that overexpression is not dependent on genetic or epigenetic modifications at the EEF1A2 locus. We suggest that the cause of overexpression of eEF1A2 may be the inappropriate expression of a trans-acting factor. The oncogenicity of eEF1A2 may be related either to its role in protein synthesis or to potential non-canonical functions.

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“…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). We have previously identified eeF1a2 as a candidate oncogene in human hepatocarcinogenesis and demonstrated that EEF1A2 overexpression was strongly associated with the survival probability of HCC patients (20,21).…”

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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Peptide Elongation Factor eEF1A-2/S1 Expression in Cultured Differentiated Myotubes and Its Protective Effect against Caspase- 3-mediated Apoptosis

Cited by 122 publications

References 35 publications

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

Protumorigenic role of Timeless in hepatocellular carcinoma

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