Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
Elongation follows the assembly of the 80S initiation complex. The process of elongation is controlled by eukaryotic elongation factors (eEFs) and uses the codons of the mRNA as a template to recruit the correct sequence of tRNA. Elongation proceeds in a cycle involving (i) binding of activated tRNA (i.e. tRNA bound with its respective amino acid), (ii) peptide bond formation and (iii) release of the inactive tRNA. The ribosome moves along the mRNA in this manner until a stop codon is reached, at which point the process is terminated by eukaryotic release factors (eRFs). Beyond the acute regulation of protein translation, the biogenesis and activity of organelles, including the ribosomes and lysosomes (autophagy, relevant to protein degradation as described later), and the importance of skeletal muscle satellite cells for adaptation (Chapter 13), are some of the emerging areas of interest in this field (10).
Anti-Cancer Agents from Natural Sources
Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg in Promising Drug Molecules of Natural Origin, 2020
Exotoxin A (ETA) is an exotoxin produced by Pseudomonas aeruginosa, a common gram-negative bacterium that is present in soil and water worldwide (WebMD, 2018). ETA works by catalyzing the ADP-ribosyltransferase of eukaryotic elongation factor-2 (eEF2) protein. This prevents protein synthesis on the targeted host (Yates et al., 2004). Because of this, recent studies focused to validate the anticancer potential of ETA on cancerous cells. Ellazeik et al. (2013) successfully enhanced ETA’s toxicity through a mutation of the three wild-type isolates. In vitro breast carcinoma cells MCF-7 was treated with ETA and growth inhibition was noted at a relatively higher concentration. ETA prevented protein synthesis in MCF-7 cells. To further validate the efficacy of ETA on other malignant cells lines, Goldufsky et al. (2015) treated B16, HeLa, Calu-3, and EMT6 among others in diverse concentrations of ETA. The study revealed a higher concentration of lactate dehydrogenase (LDH), indicating a high level of cytotoxicity. The same research group conducted in vivo experiment using mice transplanted with B16 melanoma cells. On treatment with ETA, induction of cytotoxicity and tumor growth delay were observed. This determined the high efficacy of ETA as an anticancer agent.
Cytotoxic Phenanthridone Alkaloid Constituents of the Amaryllidaceae
Spyridon E. Kintzios, Maria G. Barberaki, Evangelia A. Flampouri in Plants That Fight Cancer, 2019
Narciclasine (11) also exhibited good IC50 growth-inhibitory values of 30–100 μM against various melanoma cells by targeting the elongation factor eEF1A (Van Goietsenoven et al. 2010). This result is significant since melanomas exhibit intrinsic resistance to pro-apoptotic stimuli and consequently respond poorly to conventional adjuvant therapies (Van Goietsenoven et al. 2010). Found in abundance in eukaryote cells, eEF1A (eukaryotic translation elongation factor 1 alpha) binds to and delivers aa-tRNA (aminoacyl-tRNA) to the vacant A-site of elongating ribosomes (Van Goietsenoven et al. 2010). It also performs several functions in actin cytoskeleton organization, cell migration, cell morphology, protein synthesis, and cell death (Van Goietsenoven et al. 2010). It was shown that eEF1A targeting with narciclasine (at 50 nM) leads to pronounced actin cytoskeleton disorganization and subsequent cytokinesis impairment, as well as protein synthesis impairment via the initiation and elongation steps (Van Goietsenoven et al. 2010). Further study of the apoptosis-inducing ability of narciclasine (11) was carried out in HL60 and HSC2 (human squamous carcinoma) cells against which it had potent cytotoxic effects (IC50 0.018 and 0.05 μM, respectively) (Jitsuno et al. 2011). The apoptotic mode of cell death in this instance was indicated by characteristic morphological changes including, cell shrinkage, chromatin condensation, ladder-like fragmentation pattern for internucleosomal DNA, as well as caspase-3 activation (Jitsuno et al. 2011).
Targeting CD123 in BPDCN: an emerging field
Published in Expert Review of Hematology, 2021
Adam J DiPippo, Nathaniel R Wilson, Naveen Pemmaraju
After binding to its natural receptor (CD123 or IL3Rα), tagraxofusp is then internalized, endocytosed into the cell, and localized in endosomes where the acidic environment cleaves DT388 from its linker and is transported into the cytosol [57,58]. Here, DT388 induces ADP ribosylation of elongation factor 2 (eEF2), which has the essential function of catalyzing the translocation of RNA on the 80S ribosome. Of note, human eEF2 has a unique and conserved diphthamide residue that DT388 and other toxins (i.e. exotoxin A) can bind as a substrate and irreversibly inhibit eEF2 function [57,59]. Nonfunctional eEF2 results in cessation of cellular protein synthesis and induces cell death [19,37,57,60,61]. Additionally, tagraxofusp is not a substrate for common drug efflux pumps or P-glycoprotein, which reduces the risk of inherent cellular resistance [62, 63].
EloA promotes HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity
Published in Platelets, 2022
Lanyue Hu, Weiwei Zhang, Zheng Xiang, Yali Wang, Cheng Zeng, Xiaojie Wang, Chengning Tan, Yichi Zhang, Fengjie Li, Yanni Xiao, Luping Zhou, Jiuxuan Li, Chun Wu, Yang Xiang, Lixin Xiang, Xiaomei Zhang, Xueying Wang, Wuchen Yang, Maoshan Chen, Qian Ran, Zhongjun Li, Li Chen
The human Elongin A (EloA) gene is located on chromosome 1p36 and encodes the transcription elongation protein EloA, which serves as the substrate recognition subunit of a CUL5/RBX2-containing Cullin-RING ubiquitin ligase that targets Pol II stalled at sites of DNA damage and perhaps other impediments [11,12]. The EloA has also been reported to act as a transcriptional activity subunit of the transcription elongation factor B (SIII) complex that stimulates the overall RNA chain synthesis rate by suppressing the frequency of transient pausing of RNA polymerase II (pol II) [13–15]. While the transcription elongation activity of EloA is related to the expression of its downstream genes, such as ATF3 and p21 [16,17], heat shock gene HSP70 [18] and retinoic acid-induced genes including Neurogenin1, Neurogenin2, NeuroD4, and Hoxa [12]. Furthermore, many biological processes have been reported to involve the EloA, such as the neuronal differentiation and development [12], early embryonic development and cellular senescence [19], and normal cell cycle progression [20]. However, the roles and molecular mechanism of EloA in MK development, especially the polyploid formation, are still unknown and require further investigations.
The application of gene silencing in proteomics: from laboratory to clinic
Published in Expert Review of Proteomics, 2018
Maura Brioschi, Cristina Banfi
In the study from Hamey et al., the authors knocked out, using the CRISPR/Cas9 system, the genes encoding two putative methyltransferases of elongation factor 1A (METTL21B and METTL23), in a human immortalized myelogenous leukemia cell line (K562). Global proteomic analysis of METTL21B knockout cells was performed using SILAC followed by SDS–PAGE, for protein separation, and liquid chromatography (LC)/MS, for protein identification. The results revealed alterations in biological processes related to elongation factor 1A functions, including an upregulation of large ribosomal subunit proteins. Furthermore, analysis of protein methylation by MS revealed that METTL21B is responsible for elongation factor 1A methylation at a specific site (Lys 165) [78].
Related Knowledge Centers
- Bacteria
- Peptide
- Peptide Bond
- Ribosome
- Amino Acid
- Protein Biosynthesis
- Translation
- Ef-Tu
- Ef-Ts
- Ef-G