A5002284937- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- RNA Research and Splicing
- interferon and immune responses
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- Polyamine Metabolism and Applications
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- Virus-based gene therapy research
- Cancer-related Molecular Pathways
- CRISPR and Genetic Engineering
- Cancer-related molecular mechanisms research
- Cancer, Hypoxia, and Metabolism
- RNA Interference and Gene Delivery
- Viral Infectious Diseases and Gene Expression in Insects
- Protein Tyrosine Phosphatases
- Tuberous Sclerosis Complex Research
- Heat shock proteins research
- NF-κB Signaling Pathways
- Hippo pathway signaling and YAP/TAZ
- Genomics, phytochemicals, and oxidative stress
- GABA and Rice Research
- Amino Acid Enzymes and Metabolism
McGill University
2016-2025
Jewish General Hospital
2014-2025
Faculty (United Kingdom)
2012-2014
Institute for Medical Research
2006-2013
University of Thessaly
2010
Angelina College
2010
Memorial Sloan Kettering Cancer Center
2005
Cleveland Clinic
2005
Case Western Reserve University
2004
University School
2004
Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step regulation stress phosphorylation translation initiation factor eIF2α on Ser51, leads inhibition new Here we report that exposure human diploid fibroblasts transformed cells led eIF2α,...
The double-stranded RNA-dependent protein kinase (dsRNA-PK) is thought to be a key mediator of the antiviral and antiproliferative effects interferons (IFNs). Studies examining physiological function suggest that it participates in cell growth differentiation by regulating synthesis. Autophosphorylation consequent activation dsRNA-PK vitro vivo result phosphorylation α subunit eukaryotic initiation factor-2 (eIF-2) inhibition Expression functionally defective mutant human NIH 3T3 cells...
The tumor suppressor p53, a sensor of multiple forms cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis. We demonstrate that endoplasmic reticulum (ER) stress inhibits p53-mediated mechanism inhibition involves the increased cytoplasmic localization p53 due phosphorylation at serine 315 and 376, which mediated glycogen synthase kinase-3 β (GSK-3β). ER induces GSK-3β binding in nucleus enhances suppressor. Inhibition apoptosis...
The interferon-inducible, double-stranded RNA-dependent protein kinase PKR has been implicated in anti-viral, anti-tumor, and apoptotic responses. Others have attempted to examine the requirement of these roles by targeted disruption at amino terminal-encoding region <i>Pkr</i> gene. By using a strategy that aims catalytic domain PKR, we generated mice are genetically ablated for functional PKR. Similar other mouse model disruption, observed no consequences loss on tumor suppression....
The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes stress to which an unfolded protein response is activated render cell survival or apoptosis (chronic stress). Transcriptional and translational reprogramming tightly regulated during ensure specific gene expression. master regulator this PERK/eIF2α/ATF4 signaling where eIF2α phosphorylated (eIF2α-P) by kinase PERK. This signal leads global shutdown, but it also enables translation transcription factor...
Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that mediated via phosphorylation translation initiation factor eIF2α. It reported here chronic correlated increased islet and apoptosis vivo. Paradoxically, induced an anabolic transcription program overcome translational repression by eIF2α phosphorylation. This...
Abstract Phosphorylation of the α subunit translation initiation factor eIF2 at serine 51 (eIF2 P) is a master regulator cell adaptation to various forms stress with implications in antitumor treatments chemotherapeutic drugs. Herein, we demonstrate that genetic loss kinases PERK and GCN2 or impaired P by means renders immortalized mouse fibroblasts as well human tumor cells increasingly susceptible death oxidative stress. We also show facilitates Akt activation subjected insults. However,...
Abstract Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast NANOG , SNAIL NODAL transcripts manifest multiple isoforms characterized by different 5’ Untranslated Regions (5’UTRs), translation subset these stimulated under hypoxia. The accumulation the corresponding proteins induces plasticity “fate-switching” toward stem cell-like phenotypes....
Abstract Ternary complex (TC) and eIF4F assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation mTOR/4E-BP pathway, respectively. How TC coordinated, however, remains largely unknown. We show that mTOR suppresses of mRNAs activated under short-term stress wherein recycling is attenuated phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β recruitment NCK1 to eIF2, decreases bolsters recycling....
In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes high degree heterogeneity associated with disease. Specifically, focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as potential vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment...
The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. double-stranded-RNA-activated protein PKR is serine/threonine interferon (IFN)-inducible kinase which an important regulation of gene expression at both transcriptional translational levels. Since cross talk between IFN-inducible proteins had already been established, we investigated whether how function was modulated by PKR. We analyzed several cell lines derived from PKR+/+ PKR-/- mouse...
A cornerstone of the antiviral interferon response is phosphorylation eukaryotic initiation factor (eIF)2alpha. This limits availability eIF2.GTP.Met-tRNA(i)(Met) ternary complexes, reduces formation 43S preinitiation and blocks viral (and most cellular) mRNA translation. However, many viruses have developed counterstrategies that circumvent this cellular response. Herein, we characterize a novel class translation inhibitors block complex prevent assembly complexes. We find driven by HCV...
Inhibition of a stress-response pathway renders tumor cells more susceptible to death induced by inhibitors phosphoinositide 3-kinase signaling.
Various forms of stress induce pathways that converge on the phosphorylation alpha (α) subunit eukaryotic translation initiation factor eIF2 at serine 51 (S51), a modification results in global inhibition protein synthesis. In many cases eIF2α is biological response facilitates cells to cope with stressful environments. Glucose deficiency, an important form stress, associated induction apoptosis. Herein, we demonstrate key step maintaining balance between life and death glucose-deficient...
Phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) is mediated by a family kinases that respond to various forms environmental stress. The eIF2alpha are critical for mRNA translation, cell proliferation, and apoptosis. Activation the tumor suppressor p53 results in cycle arrest apoptosis response types We previously showed that, unlike majority stress responses stabilize activate p53, induction endoplasmic reticulum leads degradation through an Mdm2-dependent mechanism. Here,...
Regulation of cell volume is great importance because persistent swelling or shrinkage leads to death. Tissues experience hypertonicity in both physiological (kidney medullar cells) and pathological states (hypernatremia). Hypertonicity induces an adaptive gene expression program that recovery apoptosis under stress. We show the commitment controlled by phosphorylation translation initiation factor eIF2α, master regulator stress response. Studies with cultured mouse fibroblasts cortical...