Search results for "eIF2"
showing 9 items of 9 documents
Inappropriate translation inhibition and P-body formation cause cold-sensitivity in tryptophan-auxotroph yeast mutants
2017
In response to different adverse conditions, most eukaryotic organisms, including Saccharomyces cerevisiae, downregulate protein synthesis through the phosphorylation of eIF2α (eukaryotic initiation factor 2α) by Gcn2, a highly conserved protein kinase. Gcn2 also controls the translation of Gcn4, a transcription factor involved in the induction of amino acid biosynthesis enzymes. Here, we have studied the functional role of Gcn2 and Gcn2-regulating proteins, in controlling translation during temperature downshifts of TRP1 and trp1 yeast cells. Our results suggest that neither cold-instigated amino acid limitation nor Gcn2 are involved in the translation suppression at low temperature. Howev…
Cryptotanshinone deregulates unfolded protein response and eukaryotic initiation factor signaling in acute lymphoblastic leukemia cells.
2015
Abstract Background: Unfolded protein responses (UPR) determine cell fate and are recognized as anticancer targets. In a previous research, we reported that cryptotanshinone (CPT) exerted cytotoxic effects toward acute lymphoblastic leukemia cells through mitochondria-mediated apoptosis. Purpose: In the present study, we further investigated the role of UPR in CPT-induced cytotoxicity on acute lymphoblastic leukemia cells by applying tools of pharmacogenomics and bioinformatics. Methods: Gene expression profiling was performed by mRNA microarray hybridization. Potential transcription factor binding motifs were identified in the promoter regions of the deregulated genes by Cistrome software.…
Wolcott-Rallison Syndrome
2004
Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2α (eIF2α) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in…
Consensus guidelines for the detection of immunogenic cell death
2014
Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defect…
Broadening the phenotypic spectrum and physiological insights related toEIF2S3variants
2021
Mental deficiency, epilepsy, hypogonadism, microcephaly and obesity (MEHMO) syndrome is a severe X-linked syndrome caused by pathogenic variants in EIF2S3. The gene encodes the γ subunit of the eukaryotic translation initiation factor-2, eIF2, essential for protein translation. A recurrent frameshift variant is described in severely affected patients while missense variants usually cause a moderate phenotype. We identified a novel missense variant (c.433A>G, p.(Met145Val)) in EIF2S3 in a mildly affected patient. Studies on zebrafish confirm the pathogenicity of this novel variant and three previously published missense variants. CRISPR/Cas9 knockout of eif2s3 in zebrafish embryos recapitula…
Between Scylla and Charibdis: eIF2α kinases as targets for cancer chemotherapy
2011
[EN] The eIF2 alpha kinases integrate translation initiation rates with nutrient availability, thus allowing cells to adapt to nutrient scarcity. Recent evidence has uncovered new functions of these kinases in tumour cell biology, ranging from regulation of cell cycle progression, maintenance of genome stability, control of apoptosis, and cell survival under nutrient stress and hypoxia. Accordingly, active eIF2 alpha kinases modulate the antineoplasic activity of several antitumour drugs, either by exacerbating their cytotoxic effect or by promoting chemoresistance. Understanding of eIF2 alpha kinases molecular roles may provide mechanistic insights into how tumour cells sense and adapt to …
Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain
2007
Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2α (eukaryotic translation initiation factor 2 subunit α) dephosphorylation, significantly reduced KA-induced ER stress and neuronal deathin vivo…
UNRAVELLING THE ROLES OF THE NUCLEAR PROTEIN 1 DURING ER-STRESS INDUCTION
2020
Background: NUPR1 was described as a transcriptional factor involved in the regulation of various cellular stress-response genes, playing a crucial role in the condition of the endoplasmic-reticulum (ER) stress, thus emerging as a common molecular factor of different pathologies, obesity, hepatic steatosis, and cancer. In the present work we aim to explore how NUPR1 interacts with some pivotal genes that are the major modulators of the ER stress and metabolic cell functions. In particular we investigated the biochemical and molecular effects arising from the loss of NUPR1 in ER stress physiological conditions. Methods: We used prolonged high fat diet (HFD) feeding to induce ER stress physio…
eIF2α confers cellular tolerance to S. aureus α-toxin
2015
We report on the role of conserved stress-response pathways for cellular tolerance to a pore forming toxin. First, we observed that small molecular weight inhibitors including of eIF2α-phosphatase, jun-N-terminal kinase (JNK), and PI3-kinase sensitized normal mouse embryonal fibroblasts (MEFs) to the small pore forming S. aureus α-toxin. Sensitization depended on expression of mADAM10, the murine ortholog of a proposed high-affinity receptor for α-toxin in human cells. Similarly, eIF2α (S51A/S51A) MEFs, which harbor an Ala knock-in mutation at the regulated Ser51 phosphorylation site of eukaryotic translation initiation factor 2α, were hyper-sensitive to α-toxin. Inhibition of translation w…