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Prevarskaya N.,French Institute of Health and Medical Research | Prevarskaya N.,Lille University of Science and Technology | Ouadid-Ahidouch H.,Laboratory of Cellular and Molecular Physiology | Skryma R.,French Institute of Health and Medical Research | And 2 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca2+ signalling is determined by the concerted action of a molecular Ca2+handling toolkit which includes: active energy-dependent Ca2+ transporters, Ca2+-permeable ion channels, Ca2+-binding and storage proteins, Ca2+dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca2+-handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca2+ concentrations or spatio-temporal patterns of Ca2+ signalling become distorted. This causes deregulation of Ca2+dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca2+ homeostasis remodelling in cancer cells as well as in identification of the key Ca2+-transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca2+ transport-targeting tools for cancer diagnosis and treatment. © 2014 The Author(s) Published by the Royal Society. Source


Ay A.-S.,Laboratory of Cellular and Molecular Physiology | Benzerdjerb N.,Laboratory of Cellular and Molecular Physiology | Sevestre H.,Laboratory of Cellular and Molecular Physiology | Ahidouch A.,Laboratory of Cellular and Molecular Physiology | And 2 more authors.
PLoS ONE | Year: 2013

Orai channels have been associated with cell proliferation, survival and metastasis in several cancers. The present study investigates the expression and the role of Orai3 in cell proliferation in non-small cell lung cancer (NSCLC). We show that Orai3 is over-expressed in cancer tissues as compared to the non-tumoral ones. Furthermore, Orai3 staining is stronger in high grade tumors. Pharmacological inhibition or knockdown of Orai3 significantly reduced store operated calcium entry (SOCE), inhibited cell proliferation and arrested cells of two NSCLC cell lines in G0/G1 phase. These effects were concomitant with a down-regulation of cyclin D1, cyclin E, CDK4 and CDK2 expression. Moreover, Orai3 silencing decreased Akt phosphorylation levels. In conclusion, Orai3 constitutes a native SOCE pathway in NSCLC that controls cell proliferation and cell cycle progression likely via Akt pathway. © 2013 Ay et al. Source


Morin G.,University of Picardie Jules Verne | Bruechle N.O.,RWTH Aachen | Singh A.R.,University of Picardie Jules Verne | Knopp C.,RWTH Aachen | And 17 more authors.
Human Mutation | Year: 2014

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca2+ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca2+ levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance. © 2014 The Authors. *Human Mutation published by Wiley Periodicals, Inc. Source

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