10 results on '"Nassour H"'
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2. Pepducin UT-Pep2 a biased allosteric agonist of Urotensin-II receptor
- Author
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Carotenuto, A., primary, Hoang, T.A., additional, Nassour, H., additional, Martin, R.D., additional, Billard, E., additional, Myriam, L., additional, Novellino, E., additional, Tanny, J.C., additional, Fournier, A., additional, Hebert, T.E., additional, and Chatenet, D., additional
- Published
- 2019
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3. Evidence for heterodimerization and functional interaction of the urotensin II and the angiotensin II type 1 receptors.
- Author
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Nassour H, Pétrin D, Devost D, Billard E, Sleno R, Hébert TE, and Chatenet D
- Subjects
- Humans, Angiotensin II, HEK293 Cells, Receptor, Angiotensin, Type 1, Urotensins
- Abstract
Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling remains incompletely understood. Notably, the putative interaction between hUT and hAT1R could engender reciprocal allosteric modulation of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. Using a combination of co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors, we first demonstrated the physical interaction between hUT and hAT1R. Next, to analyze how this functional interaction regulated proximal and distal hUT- and hAT1R-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. We observed that hUT-hAT1R heterodimers triggered distinct signaling outcomes compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R has no impact on hUII-induced G
q activation but significantly reduced the potency and efficacy of Ang II to mediate Gq activation. Interestingly, URP, the second hUT endogenous ligand, produce a distinct signaling signature compared to hUII at hUT-hAT1R. Our results therefore suggest that assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Altogether, our work, which potentially explains the interplay observed in native cells and tissues, validates such complexes as potential targets to promote the design of compounds that can modulate heterodimer function selectively., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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4. Lipidated peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as biased allosteric ligands.
- Author
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Nassour H, Hoang TA, Martin RD, Dallagnol JCC, Billard É, Létourneau M, Novellino E, Carotenuto A, Allen BG, Tanny JC, Fournier A, Hébert TE, and Chatenet D
- Subjects
- Allosteric Regulation, Cell Proliferation, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins genetics, Ligands, Peptide Hormones chemistry, Peptide Hormones genetics, Peptides chemistry, Protein Conformation, alpha-Helical, Receptors, G-Protein-Coupled genetics, Signal Transduction, Intracellular Signaling Peptides and Proteins metabolism, Peptide Hormones metabolism, Peptides metabolism, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled metabolism
- Abstract
Over the last decade, the urotensinergic system, composed of one G protein-coupled receptor and two endogenous ligands, has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases. Indeed, this system is associated with various biomarkers of cardiovascular dysfunctions and is involved in changes in cardiac contractility, fibrosis, and hypertrophy contributing, like the angiotensinergic system, to the pathogenesis and progression of heart failure. Significant investment has been made toward the development of clinically relevant UT ligands for therapeutic intervention, but with little or no success to date. This system therefore remains to be therapeutically exploited. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics; therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study hUT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of the receptor (hUT-Pep2 and [Trp
1 , Leu2 ]hUT-Pep3, respectively), were synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1 , Leu2 ]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and, to a lesser extent, IP1 production, and stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate human urotensin II (hUII)- and urotensin II-related peptide (URP)-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue for the design of allosteric ligands selectively targeting hUT signaling potentially., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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5. Spt5 Phosphorylation and the Rtf1 Plus3 Domain Promote Rtf1 Function through Distinct Mechanisms.
- Author
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Chen JJ, Mbogning J, Hancock MA, Majdpour D, Madhok M, Nassour H, Dallagnol JC, Pagé V, Chatenet D, and Tanny JC
- Subjects
- Phosphorylation, Positive Transcriptional Elongation Factor B metabolism, RNA Polymerase II metabolism, Transcription, Genetic genetics, Transcriptional Elongation Factors metabolism, Chromosomal Proteins, Non-Histone metabolism, Schizosaccharomyces metabolism, Schizosaccharomyces pombe Proteins metabolism, Transcriptional Elongation Factors genetics
- Abstract
Rtf1 is a conserved RNA polymerase II (RNAPII) elongation factor that promotes cotranscriptional histone modification, RNAPII transcript elongation, and mRNA processing. Rtf1 function requires the phosphorylation of Spt5, an essential RNAPII processivity factor. Spt5 is phosphorylated within its C-terminal domain (CTD) by cyclin-dependent kinase 9 (Cdk9), the catalytic component of positive transcription elongation factor b (P-TEFb). Rtf1 recognizes phosphorylated Spt5 (pSpt5) through its Plus3 domain. Since Spt5 is a unique target of Cdk9 and Rtf1 is the only known pSpt5-binding factor, the Plus3/pSpt5 interaction is thought to be a key Cdk9-dependent event regulating RNAPII elongation. Here, we dissect Rtf1 regulation by pSpt5 in the fission yeast Schizosaccharomyces pombe We demonstrate that the Plus3 domain of Rtf1 (Prf1 in S. pombe ) and pSpt5 are functionally distinct and that they act in parallel to promote Prf1 function. This alternate Plus3 domain function involves an interface that overlaps the pSpt5-binding site and that can interact with single-stranded nucleic acid or with the polymerase-associated factor (PAF) complex in vitro We further show that the C-terminal region of Prf1, which also interacts with PAF, has a similar parallel function with pSpt5. Our results elucidate unexpected complexity underlying Cdk9-dependent pathways that regulate transcription elongation., (Copyright © 2020 American Society for Microbiology.)
- Published
- 2020
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6. Towards Targeting the Urotensinergic System: Overview and Challenges.
- Author
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Nassour H, Iddir M, and Chatenet D
- Subjects
- Animals, Drug Delivery Systems, Humans, Intracellular Signaling Peptides and Proteins agonists, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins metabolism, Ligands, Peptide Hormones metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction drug effects, Urotensins metabolism, Peptide Hormones agonists, Peptide Hormones antagonists & inhibitors, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled antagonists & inhibitors, Urotensins agonists, Urotensins antagonists & inhibitors
- Abstract
The urotensinergic system, comprised of a G protein-coupled receptor (UT) and two endogenous ligands named urotensin II (UII) and urotensin II-related peptide (URP), has garnered significant attention due to its involvement in the initiation and/or the evolution of various diseases. Accordingly, multiple studies using animal models have demonstrated that UT antagonists may have utility as potential therapeutic agents for treating atherosclerosis, pulmonary arterial hypertension, heart failure, and cancer. Unfortunately, clinical investigations of UT antagonist candidates showed limited efficacy in humans. This system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. Here, we discuss various hypotheses that could explain the in vivo failure of UT antagonists., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
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7. Insights into a novel nuclear function for Fascin in the regulation of the amino-acid transporter SLC3A2.
- Author
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Saad A, Bijian K, Qiu D, da Silva SD, Marques M, Chang CH, Nassour H, Ramotar D, Damaraju S, Mackey J, Bismar T, Witcher M, and Alaoui-Jamali MA
- Subjects
- Breast Neoplasms metabolism, Cell Line, Tumor, Cell Nucleus metabolism, DNA-Binding Proteins, HEK293 Cells, Histones metabolism, Humans, Nuclear Proteins metabolism, Phosphorylation, TOR Serine-Threonine Kinases metabolism, Transcriptome, Carrier Proteins metabolism, Fusion Regulatory Protein 1, Heavy Chain metabolism, Gene Expression, Gene Expression Regulation, Microfilament Proteins metabolism
- Abstract
Fascin 1 (FSCN1) is a cytoskeleton-associated protein recognized to function primarily in the regulation of cytoskeleton structure and formation of plasma membrane protrusions. Here we report a novel nuclear function for Fascin 1. Biochemical studies and genome wide localization using ChIP-seq identified phosphorylated Fascin 1 (pFascin) in complexes associated with transcription and that it co-localizes with histone H3 Lys4 trimethylation (H3K4me3) on chromatin. Gene expression profiling identified genes affected by Fascin 1 including SLC3A2, a gene encoding for a plasma membrane transporter that regulates intracellular amino acid levels. RbBP5, a subunit of the H3K4 histone methyltransferase (HMT) complex was found to interact with Fascin 1 supporting its role in H3K4me3 establishment at target genes. Moreover, we show that changes to SLC3A2 levels affect amino acid-mediated mTORC1 activation. These results reveal that Fascin 1 has a yet undiscovered nuclear function as an epigenetic modulator of genes essential for amino acid metabolism.
- Published
- 2016
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8. Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression.
- Author
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Nassour H, Wang Z, Saad A, Papaluca A, Brosseau N, Affar el B, Alaoui-Jamali MA, and Ramotar D
- Subjects
- Cell Nucleus metabolism, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Hydrogen Peroxide pharmacology, Neoplasm Invasiveness, Neoplasm Metastasis, Oxidative Stress, Promoter Regions, Genetic, Stomach Neoplasms metabolism, Transcriptional Activation, DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism, Interleukin-8 genetics, NF-kappa B metabolism, Peroxiredoxins genetics, Peroxiredoxins metabolism, Stomach Neoplasms genetics
- Abstract
APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis.
- Published
- 2016
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9. Escherichia coli STb enterotoxin dislodges claudin-1 from epithelial tight junctions.
- Author
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Nassour H and Dubreuil JD
- Subjects
- Cell Line, Colon cytology, Colon metabolism, Culture Media chemistry, Cytoplasm metabolism, Humans, Phosphorylation drug effects, Tight Junctions drug effects, Bacterial Toxins pharmacology, Claudin-1 metabolism, Enterotoxigenic Escherichia coli metabolism, Enterotoxins pharmacology, Escherichia coli Proteins pharmacology, Tight Junctions metabolism
- Abstract
Enterotoxigenic Escherichia coli produce various heat-labile and heat-stable enterotoxins. STb is a low molecular weight heat-resistant toxin responsible for diarrhea in farm animals, mainly young pigs. A previous study demonstrated that cells having internalized STb toxin induce epithelial barrier dysfunction through changes in tight junction (TJ) proteins. These modifications contribute probably to the diarrhea observed. To gain insight into the mechanism of increased intestinal permeability following STb exposure we treated human colon cells (T84) with purified STb toxin after which cells were harvested and proteins extracted. Using a 1% Nonidet P-40-containing solution we investigated the distribution of claudin-1, a major structural and functional TJ protein responsible for the epithelium impermeability, between membrane (NP40-insoluble) and the cytoplasmic (NP-40 soluble) location. Using immunoblot and confocal microscopy, we observed that treatment of T84 cell monolayers with STb induced redistribution of claudin-1. After 24 h, cells grown in Ca++-free medium treated with STb showed about 40% more claudin-1 in the cytoplasm compare to the control. Switching from Ca++-free to Ca++-enriched medium (1.8 mM) increased the dislodgement rate of claudin-1 as comparable quantitative delocalization was observed after only 6 h. Medium supplemented with the same concentration of Mg++ or Zn++ did not affect the dislodgement rate compared to the Ca++-free medium. Using anti-phosphoserine and anti-phosphothreonine antibodies, we observed that the loss of membrane claudin-1 was accompanied by dephosphorylation of this TJ protein. Overall, our findings showed an important redistribution of claudin-1 in cells treated with STb toxin. The loss of phosphorylated TJ membrane claudin-1 is likely to be involved in the increased permeability observed. The mechanisms by which these changes are brought about remain to be elucidated.
- Published
- 2014
- Full Text
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10. UVC-induced stress granules in mammalian cells.
- Author
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Moutaoufik MT, El Fatimy R, Nassour H, Gareau C, Lang J, Tanguay RM, Mazroui R, and Khandjian EW
- Subjects
- Animals, Biomarkers metabolism, Cell Proliferation radiation effects, Cytoplasm metabolism, DNA biosynthesis, Dose-Response Relationship, Radiation, Mice, NIH 3T3 Cells, Cytoplasm radiation effects, Ultraviolet Rays
- Abstract
Stress granules (SGs) are well characterized cytoplasmic RNA bodies that form under various stress conditions. We have observed that exposure of mammalian cells in culture to low doses of UVC induces the formation of discrete cytoplasmic RNA granules that were detected by immunofluorescence staining using antibodies to RNA-binding proteins. UVC-induced cytoplasmic granules are not Processing Bodies (P-bodies) and are bone fide SGs as they contain TIA-1, TIA-1/R, Caprin1, FMRP, G3BP1, PABP1, well known markers, and mRNA. Concomitant with the accumulation of the granules in the cytoplasm, cells enter a quiescent state, as they are arrested in G1 phase of the cell cycle in order to repair DNA damages induced by UVC irradiation. This blockage persists as long as the granules are present. A tight correlation between their decay and re-entry into S-phase was observed. However the kinetics of their formation, their low number per cell, their absence of fusion into larger granules, their persistence over 48 hours and their slow decay, all differ from classical SGs induced by arsenite or heat treatment. The induction of these SGs does not correlate with major translation inhibition nor with phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). We propose that a restricted subset of mRNAs coding for proteins implicated in cell cycling are removed from the translational apparatus and are sequestered in a repressed form in SGs.
- Published
- 2014
- Full Text
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