Deletion of eIF2β lysine stretches creates a dominant negative that affects the translation and proliferation in human cell line: A tool for arresting the cell growth

Salton, Gabrielle Dias; Laurino, Claudia Cilene Fernandes Correia; Mega, Nicolás Oliveira; Cañedo, Andrés Delgado; Setterblad, Niclas; Carmagnat, Maryvonnick; Xavier, Ricardo Machado; Cirne-Lima, Elizabeth Obino; Lenz, Guido; Henriques, João Antônio Pêgas; Laurino, Jomar Pereira

doi:10.1080/15384047.2017.1345383

Cited by 8 publications

(6 citation statements)

References 73 publications

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“…Consistent with our hypothesis, an array of studies have demonstrated that eIF4A3 can promote the back-splicing reaction by directly interacting with the flanking sequence of circularizing exons in mammalian cells ( 92–94 ). Since several eIFs have been reported as nucleocytoplasmic shuttling proteins ( 95–97 ), the nuclear functions of eIFs should be taken into consideration in future.…”

Section: Discussionmentioning

confidence: 99%

eIF3j inhibits translation of a subset of circular RNAs in eukaryotic cells

Song

Lin

et al. 2022

Nucleic Acids Research

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Increasing studies have revealed that a subset of circular RNAs (circRNAs) harbor an open reading frame and can act as protein-coding templates to generate functional proteins that are closely associated with multiple physiological and disease-relevant processes, and thus proper regulation of synthesis of these circRNA-derived proteins is a fundamental cellular process required for homeostasis maintenance. However, how circRNA translation initiation is coordinated by different trans-acting factors remains poorly understood. In particular, the impact of different eukaryotic translation initiation factors (eIFs) on circRNA translation and the physiological relevance of this distinct regulation have not yet been characterized. In this study, we screened all 43 Drosophila eIFs and revealed the conflicting functions of eIF3 subunits in the translational control of the translatable circRNA circSfl: eIF3 is indispensable for circSfl translation, while the eIF3-associated factor eIF3j is the most potent inhibitor. Mechanistically, the binding of eIF3j to circSfl promotes the disassociation of eIF3. The C-terminus of eIF3j and an RNA regulon within the circSfl untranslated region (UTR) are essential for the inhibitory effect of eIF3j. Moreover, we revealed the physiological relevance of eIF3j-mediated circSfl translation repression in response to heat shock. Finally, additional translatable circRNAs were identified to be similarly regulated in an eIF3j-dependent manner. Altogether, our study provides a significant insight into the field of cap-independent translational regulation and undiscovered functions of eIF3.

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Section: Discussionmentioning

confidence: 99%

eIF3j inhibits translation of a subset of circular RNAs in eukaryotic cells

Song

Lin

et al. 2022

Nucleic Acids Research

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“…It is also possible that eIF2β mediates autophagy defects via mechanisms independent of ISR, since eIF2β has functions independent of eIF2 39,40 . For example, suppression of eIF2β has been reported to slow down cancer cell growth 39 . In developing neurons, eIF2β can directly interact with the translational repressor Kra to regulate midline axon guidance 40 .…”

Section: Discussionmentioning

confidence: 99%

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Shinno,

Miura,

Iijima

et al. 2024

Preprint

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Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. UsingDrosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of translation and protein degradation. Axons with mitochondrial depletion showed aggregation of synaptic vesicles, abnormal protein accumulation, and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found eIF2β was upregulated by depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2a, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression ofeIF2βphenocopied the autophagic defects and neuronal dysfunctions, and loweringeIF2βexpression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.

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“…In in vitro experiments, the knockdown of eIF2β manipulations induced G1 cell cycle arrest in both NCI-H358 and NCI-H460 cells [ 23 ]. Deleting the polylysine stretches in the amino-terminal region of eIF2β decreased protein synthesis, inhibited cell proliferation and viability, increased cell death, and induced G2 cell cycle arrest in Hek293TetR cells [ 24 ]. Interestingly, we noticed that the levels of EIF2β in somatotroph adenomas were related to the disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas

Chen

Yao

et al. 2022

IJMS

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Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.

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Deletion of eIF2β lysine stretches creates a dominant negative that affects the translation and proliferation in human cell line: A tool for arresting the cell growth

Cited by 8 publications

References 73 publications

eIF3j inhibits translation of a subset of circular RNAs in eukaryotic cells

eIF3j inhibits translation of a subset of circular RNAs in eukaryotic cells

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas

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