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21 results on '"MESH: Sphingosine"'

1. Anticancer activity of FTY720: Phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D

Author

Kevin R. Lynch, Jean Sébastien Saulnier-Blache, Volker Brinkmann, Wouter H. Moolenaar, Laurens A. van Meeteren, Simon, Marie Francoise, Division of Cellular Biochemistry and Center for Biomedical Genetics, Netherlands Cancer Institute, Autoimmunity and Transplantation, Novartis Institutes for BioMedical Research (NIBR), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology, and University of Virginia

Subjects
Cancer Research, Phosphodiesterase Inhibitors, MESH: Pyrophosphatases, Angiogenesis, MESH: Multienzyme Complexes, MESH: Phosphodiesterase Inhibitors, MESH: Phosphodiesterase I, Mice, chemistry.chemical_compound, Sphingosine, hemic and lymphatic diseases, Lysophosphatidic acid, MESH: Animals, Neoplasm Metastasis, Pyrophosphatases, Receptor, Neovascularization, Pathologic, Phosphodiesterase, Organophosphates, Oncology, Phosphodiesterase I, Female, lipids (amino acids, peptides, and proteins), MESH: Sphingosine, Autotaxin, medicine.medical_specialty, MESH: Phosphoric Acid Esters, Antineoplastic Agents, Biology, Article, MESH: Lysophospholipids, Multienzyme Complexes, MESH: Mice, Inbred C57BL, In vivo, Internal medicine, medicine, Animals, Humans, MESH: Mice, MESH: Humans, Phosphoric Diester Hydrolases, Lipid signaling, MESH: Neoplasm Metastasis, Mice, Inbred C57BL, Endocrinology, chemistry, Cancer research, MESH: Antineoplastic Agents, Lysophospholipids, MESH: Neovascularization, Pathologic, MESH: Phosphoric Diester Hydrolases, MESH: Female
Abstract

International audience; FTY720 is an immunomodulator that is phosphorylated in vivo and inhibits lymphocyte mobilization by targeting sphingosine 1-phospate receptors. At doses higher than required for immunomodulation, FTY720 inhibits tumor progression through an unknown mechanism. Here we show that FTY720-phosphate is a competitive inhibitor (Ki approximately 0.2microM) of autotaxin (ATX or NPP2), a nucleotide phosphodiesterase/pyrophosphatase (NPP) that enhances metastasis and angiogenesis and acts as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA). FTY720-phosphate did no affect the activity of NPP1, the closest relative of ATX. After oral administration in mice, FTY720 (3mg/kg) significantly reduced plasma LPA levels. These results suggest that FTY720 may exert its anticancer effects, at least in part, by targeting the ATX-LPA axis.

Published
2008
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2. Effets du PACAP et du C2- céramide sur la motilité des neurones en grain du cervelet : Rien ne sert de courir, il faut partir à point

Author

Magalie Bénard, Ludovic Galas, Hubert Vaudry, Nicolas Aubert, Anthony Falluel-Morel, Bruno J. Gonzalez, Alain Fournier, Magali Basille, David Vaudry, Marc Fontaine, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Maylin, Françoise

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Humans, Chemistry, MESH: Models, Biological, MESH: Neurons, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Cerebellum, General Biochemistry, Genetics and Molecular Biology, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Sphingosine, MESH: Cell Movement
Published
2005
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3. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Author

Olivier Cuvillier, Marie-Bernadette Delisle, Corinne Bousquet, Julie Guillermet-Guibert, Nathalie Saint-Laurent, Lise Davenne, Dimitri Pchejetski, Leyre Brizuela, Christiane Susini, Céline Guilbeau-Frugier, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
Cancer Research, Pharmacology, Deoxycytidine, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Sphingosine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Enzyme Inhibitors, MESH: Ribonucleotide Reductases, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Drug Resistance, Neoplasm, 3. Good health, Phosphotransferases (Alcohol Group Acceptor), Oncology, MESH: Cell Survival, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), MESH: Pancreatic Neoplasms, MESH: Sphingosine, medicine.drug, Ceramide, Cell Survival, Blotting, Western, Biology, Ceramides, MESH: Lysophospholipids, 03 medical and health sciences, Pancreatic cancer, MESH: Cell Proliferation, Ribonucleotide Reductases, medicine, Humans, MESH: Blotting, Western, RNA, Messenger, MESH: Tumor Cells, Cultured, 030304 developmental biology, Cell Proliferation, MESH: RNA, Messenger, MESH: Humans, Cell growth, MESH: Deoxycytidine, Cancer, medicine.disease, Sphingolipid, Gemcitabine, MESH: Phosphotransferases (Alcohol Group Acceptor), MESH: Ceramides, Pancreatic Neoplasms, chemistry, Drug Resistance, Neoplasm, Lysophospholipids
Abstract

Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.[Mol Cancer Ther 2009;8(4):809–20]

Published
2009
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4. The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Author

Stéphane Carpentier, Elodie Lafont, Thierry Levade, Yahya Salma, Marie-José Bonnafé, Yves Genisson, Nicole Therville, Nathalie Andrieu-Abadie, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Sphingomyelin, Ceramide, MESH: Cell Line, Tumor, Chromatography, Gas, MESH: Melanoma, Blotting, Western, Transferases (Other Substituted Phosphate Groups), MESH: Microscopy, Fluorescence, Apoptosis, Ceramides, 01 natural sciences, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, Sphingosine, Cell Line, Tumor, Sphingomyelin synthase, Cytotoxic T cell, MESH: Blotting, Western, Animals, Humans, MESH: Animals, MESH: Mice, Melanoma, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Humans, biology, 010405 organic chemistry, MESH: Apoptosis, MESH: Chromatography, Gas, Biological activity, Sphingolipid, MESH: Ceramides, 3. Good health, 0104 chemical sciences, Jaspine B, chemistry, Microscopy, Fluorescence, biology.protein, MESH: Transferases (Other Substituted Phosphate Groups), MESH: Sphingosine
Abstract

International audience; Marine environment has frequently afforded a variety of biologically active compounds with strong anticancer and cytotoxic properties. In the present study, the mechanism of action of Jaspine B, an anhydrophytosphingosine derivative isolated from the marine sponge Jaspis sp., was investigated. Jaspine B was able to dose- and time-dependently decrease the viability of murine B16 and human SK-Mel28 melanoma cells. On these cells, Jaspine B treatment triggered cell death by typical apoptosis as illustrated by phosphatidylserine externalization, the release of cytochrome c and caspase processing. These effects were associated with increased intracellular ceramide levels owing to perturbed ceramide metabolism. Indeed, Jaspine B exposure strongly inhibited the activity of sphingomyelin synthase (SMS), an enzyme that converts de novo ceramide into the membrane lipid sphingomyelin. Moreover, whereas Jaspine B-induced cell death was enhanced in SMS1-depleted cells, it was strongly inhibited in cells that stably overexpress human SMS1. Finally, the cytotoxic effects of Jaspine B truncated analogs were also shown to be dependent on SMS activity. Altogether, Jaspine B is able to kill melanoma cells by acting on SMS activity and consequently on ceramide formation, and may represent a new class of cytotoxic compounds with potential applications in anticancer melanoma therapy.

Published
2009
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5. FTY720 Inhibits Tumor Necrosis Factor-α-Induced Proliferation and Extracellular Signal-Regulated Kinase Phosphorylation of Human Smooth Muscle Cells

Author

Nathalie Augé, Lionel Rostaing, Mogens Thomsen, Lucie Etienne, Cindy Canivet, Robert Salvayre, Tomsen Böhler, Sylvain Galvani, Anne Nègre-Salvayre, Nassim Kamar, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie, dialyse et transplantation [Hôpital de Rangueil, Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Graft Rejection, MESH: Signal Transduction, MAPK/ERK pathway, [SDV]Life Sciences [q-bio], MESH: Muscle, Smooth, 0302 clinical medicine, Sphingosine, hemic and lymphatic diseases, Myocyte, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, MESH: Extracellular Signal-Regulated MAP Kinases, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Kinase, 3. Good health, MESH: Cell Survival, 030220 oncology & carcinogenesis, MESH: Cell Division, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH: Immunosuppressive Agents, MESH: Sphingosine, Signal transduction, Cell Division, Immunosuppressive Agents, Signal Transduction, MESH: Cells, Cultured, Cell Survival, MESH: Graft Rejection, Biology, 03 medical and health sciences, MESH: Transplantation, Homologous, Extracellular, Humans, Transplantation, Homologous, MESH: Propylene Glycols, 030304 developmental biology, Transplantation, MESH: Humans, MESH: Phosphorylation, Fingolimod Hydrochloride, Tumor Necrosis Factor-alpha, Cell growth, Muscle, Smooth, Propylene Glycols, MESH: Tumor Necrosis Factor-alpha, Cancer research, Surgery
Abstract

International audience; We investigated the effects of the sphingolipid FTY720 on tumor necrosis factor-alpha (TNF-alpha)-induced proliferation and signal transduction in human smooth muscle cells (SMC). We showed that clinically relevant concentrations of FTY720 inhibited TNF-alpha-induced SMC proliferation and extracellular signal-regulated kinase (ERK) phosphorylation. We concluded that FTY720 may be a useful drug to inhibit chronic vascular rejection.

Published
2009
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6. Ceramide production associated with retinal apoptosis after retinal detachment

Author

Thierry Levade, Maxime Cournot, Marie-Laure Ranty, Isabelle Rico-Lattes, François Malecaze, Stéphane Carpentier, Marie-Bernadette Delisle, Jean-Claude Quintyn, Simon, Marie Francoise, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Ophtalmologie [CHU Toulouse], Pôle Céphalique [CHU Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'épidémiologie [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Service d'Ophtalmologie [Hopital Purpan - Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service d'Ophtalmologie [Hopital Rangueil - Toulouse], and CHU Toulouse [Toulouse]-Hôpital de Rangueil

Subjects
Visual acuity, genetic structures, MESH: Rabbits, Apoptosis, Cell Count, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, MESH: Animals, MESH: In Situ Nick-End Labeling, Hyaluronic Acid, Retinal cell, 0303 health sciences, Viscosupplements, Retinal detachment, Anatomy, Immunohistochemistry, Sensory Systems, MESH: Retinal Detachment, Rabbits, medicine.symptom, MESH: Sphingosine, Photoreceptor Cells, Vertebrate, Ceramide, medicine.medical_specialty, Ceramides, MESH: Lysophospholipids, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ophthalmology, medicine, In Situ Nick-End Labeling, Animals, 030304 developmental biology, MESH: Hyaluronic Acid, business.industry, MESH: Cell Count, MESH: Apoptosis, Retinal Detachment, Retinal, MESH: Immunohistochemistry, medicine.disease, MESH: Ceramides, Disease Models, Animal, chemistry, 030221 ophthalmology & optometry, MESH: Photoreceptor Cells, Vertebrate, sense organs, MESH: Disease Models, Animal, Lysophospholipids, business, MESH: Viscosupplements
Abstract

International audience; BACKGROUND: During retinal detachment, premature apoptosis of photoreceptors and a loss of optimally corrected visual acuity occur. We hypothesized that retinal cell death and generation of ceramide, a pro-apoptotic lipid, would progress as a function of time following experimental retinal detachment, and undertook to define the appropriate temporal window. METHODS: Unilateral retinal detachment was induced in white New Zealand rabbits by subretinal injection of sodium hyaluronate. In experimental animals, we injected sphingosine-1-P into the vitreous 2 hours before retinal detachment. Both eyes were removed on days 1, 3 and 6 for histological and biochemical examination. The number of photoreceptors was counted in section, the level of apoptosis was assessed using the TUNEL assay, and the production of ceramide was analyzed in situ with immunohistochemistry. The concentration of ceramide was also determined on retinal homogenates using a diacylglycerol kinase assay. RESULTS: We confirmed that the average number of live photoreceptors decreased gradually after retinal detachment. In eyes pre-treated with sphingosine-1-P the number of apoptotic photoreceptors was significantly lower. The proportion of apoptotic photoreceptors (14%) remained constant as a function of time in the window studied. As compared to controls, the detached retina showed intense ceramide immunostaining that was prominent in the photoreceptors, but also present to a lesser extent in other retinal layers. The total concentration of intra-retinal ceramide increased by 40% on the first day and continued augmenting through the sixth day after retinal detachment. CONCLUSIONS: Retinal apoptosis during experimental retinal detachment is associated with in vivo production of ceramide.

Published
2008
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7. Functions of sphingolipid metabolism in mammals--lessons from genetic defects

Author

Thierry Levade, Sandra Colié, Yahya Salma, Frédérique Sabourdy, Blandine Kedjouar, Delphine Milhas, S. Caroline Sorli, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
MESH: Protein Transport, Ceramide, Lactosylceramides, Mutagenesis (molecular biology technique), Galactosylceramides, Biology, Glucosylceramides, Lipid Metabolism, Inborn Errors, MESH: Lysophospholipids, MESH: Sphingolipids, chemistry.chemical_compound, Mice, Biosynthesis, Sphingosine, Gangliosides, Animals, Humans, MESH: Animals, MESH: Sulfoglycosphingolipids, MESH: Lactosylceramides, MESH: Mice, Molecular Biology, Gene, MESH: Gangliosides, Sphingolipids, MESH: Glucosylceramides, MESH: Humans, Sulfoglycosphingolipids, MESH: Lipid Metabolism, Inborn Errors, MESH: Galactosylceramides, Lipid metabolism, MESH: Receptors, Lysosphingolipid, Cell Biology, Sphingolipid, Phenotype, Transport protein, Cell biology, Protein Transport, Receptors, Lysosphingolipid, Sphingomyelin Phosphodiesterase, chemistry, MESH: Sphingomyelin Phosphodiesterase, lipids (amino acids, peptides, and proteins), MESH: Sphingosine, Lysophospholipids
Abstract

International audience; Much is known about the pathways that control the biosynthesis, transport and degradation of sphingolipids. During the last two decades, considerable progress has been made regarding the roles this complex group of lipids play in maintaining membrane integrity and modulating responses to numerous signals. Further novel insights have been provided by the analysis of newly discovered genetic diseases in humans as well as in animal models harboring mutations in the genes whose products control sphingolipid metabolism and action. Through the description of the phenotypic consequences of genetic defects resulting in the loss of activity of the many proteins that synthesize, transport, bind, or degrade sphingolipids, this review summarizes the (patho)physiological functions of these lipids.

Published
2007
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8. Effect of FTY720 on apoptosis of smooth muscle cells

Author

Torsten Böhler, Lionel Rostaing, Cindy Canivet, Lucie Etienne, J. Guillebaud, Sylvain Galvani, Nathalie Augé, Robert Salvayre, Anne Nègre-Salvayre, Mogens Thomsen, Nassim Kamar, Jean-Claude Thiers, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Nephrologie et Transplantation Multi-Organes, CHU Toulouse [Toulouse]-Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
Programmed cell death, Necrosis, MESH: Rabbits, Apoptosis, Muscle, Smooth, Vascular, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, hemic and lymphatic diseases, medicine, Animals, Myocyte, MESH: Animals, MESH: Propylene Glycols, Transplantation, Fingolimod Hydrochloride, business.industry, MESH: Apoptosis, Arteriosclerosis, MESH: Muscle, Smooth, Vascular, musculoskeletal system, medicine.disease, Sphingolipid, 3. Good health, chemistry, MESH: Models, Animal, Propylene Glycols, 030220 oncology & carcinogenesis, Models, Animal, Immunology, cardiovascular system, Cancer research, Surgery, Rabbits, MESH: Immunosuppressive Agents, medicine.symptom, MESH: Sphingosine, business, Immunosuppressive Agents, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Hyperproliferation of smooth muscle cells (SMCs) plays a key role in allograft arteriosclerosis. This prompted us to investigate the effect of the novel immune modulator and synthetic sphingolipid FTY720 on apoptosis of SMCs. METHODS: Rabbit SMC cultures were treated with FTY720 and apoptosis and necrosis were detected by fluorescence microscopy. RESULTS: We investigated dose- and time-dependent effects of FTY720 and found that clinically relevant low doses of FTY720 (

Published
2007
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9. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities

Author

Martine Couturier, Amal Zerrad, Patrice Thérond, Anatol Kontush, M. John Chapman, Juliana A. de Souza, S. Chantepie, Anne Nègre-Salvayre, Dyslipoproteinémies et athérosclerose : Génétique, métabolisme et thérapeutique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de biochimie, Université Paris Descartes - Paris 5 (UPD5), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP], Université Paris Descartes - Paris 5 ( UPD5 ), Régulations cellulaires: lipidoses et atherosclerose., IFR 31 Louis Bugnard ( IFR 31 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
MESH : Oxidative Stress, MESH: Oxidation-Reduction, MESH: Lipoproteins, HDL3, MESH : Dyslipidemias, Apoptosis, MESH : Cholesterol, LDL, 030204 cardiovascular system & hematology, MESH: Sphingomyelins, Antioxidants, chemistry.chemical_compound, 0302 clinical medicine, Reference Values, Sphingosine, MESH : Particle Size, MESH : Sphingosine, 0303 health sciences, MESH: Oxidative Stress, MESH: Reference Values, Lipoproteins, HDL3, Sphingomyelins, Biochemistry, MESH : Cholesterol, HDL, MESH : Antioxidants, lipids (amino acids, peptides, and proteins), Cholesterol Esters, MESH : Sensitivity and Specificity, MESH: Sphingosine, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Sphingomyelin, Oxidation-Reduction, MESH: Cholesterol, LDL, MESH : Sphingomyelins, MESH: Enzyme Activation, MESH : Cholesterol Esters, MESH: Probability, MESH : Probability, Phospholipid, MESH : Reference Values, Sensitivity and Specificity, MESH: Lysophospholipids, 03 medical and health sciences, Enzyme activator, Humans, Sphingosine-1-phosphate, MESH: Particle Size, Particle Size, Dyslipidemias, Probability, 030304 developmental biology, MESH : Oxidation-Reduction, MESH: Humans, Cholesterol, MESH: Apoptosis, Cholesterol, HDL, MESH : Humans, MESH: Antioxidants, MESH: Dyslipidemias, Cholesterol, LDL, Key features, Sphingolipid, MESH: Sensitivity and Specificity, Enzyme Activation, Oxidative Stress, chemistry, MESH : Lipoproteins, HDL3, MESH : Lysophospholipids, MESH: Cholesterol Esters, Molecular Profile, Lysophospholipids, MESH : Enzyme Activation, MESH : Apoptosis
Abstract

Objective— The purpose of this study was to define heterogeneity in the molecular profile of lipids, including sphingomyelin and sphingosine-1-phosphate, among physicochemically-defined HDL subpopulations and potential relevance to antiatherogenic biological activities of dense HDL3. Methods and Results— The molecular profile of lipids (cholesteryl esters, phospholipids, sphingomyelin, and sphingosine-1-phosphate) in physicochemically-defined normolipidemic HDL subpopulations was determined by high-performance liquid chromatography and gas chromatography. As HDL particle size and molecular weight decreased with increment in density, molar lipid content diminished concomitantly. On a % basis, sphingomyelin abundance diminished in parallel with progressive increase in HDL density from HDL2b (12.8%) to HDL3c (6.2%; P P r =0.73, P r =0.58, P Conclusions— An elevated sphingosine-1-phosphate/sphingomyelin ratio is an integral feature of small dense HDL3, reflecting enrichment in sphingosine-1-phosphate, a key antiapoptotic molecule, and depletion of sphingomyelin, a structural lipid with negative impact on surface fluidity and LCAT activity. These findings further distinguish the structure and antiatherogenic activities of small, dense HDL.

Published
2007
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10. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor

Author

Laure Garrigue-Antar, Andrew R. Calver, Yannick Jacques, Myriam Baratin, Claude Carozzo, Julie Chaix, Thierry Walzer, Laura Chiossone, Eric Vivier, Elena Tomasello, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GlaxoSmithKline, Glaxo Smith Kline, Régénération tissulaire, interactions biologiques et biomatériaux (RTI2B), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Ecole Nationale Vétérinaire de Lyon (ENVL), Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR thérapeutique de Nantes, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
MESH: Killer Cells, Natural, T-Lymphocytes, Immunology, MESH: Lymphocyte Subsets, Biology, Natural killer cell, MESH: Lysophospholipids, 03 medical and health sciences, chemistry.chemical_compound, Interleukin 21, Mice, 0302 clinical medicine, Sphingosine, medicine, Immunology and Allergy, Animals, Humans, MESH: Animals, Receptor, MESH: Mice, 030304 developmental biology, 0303 health sciences, Lymphokine-activated killer cell, MESH: Humans, MESH: Receptors, Lysosphingolipid, Oligodendrocyte, Lymphocyte Subsets, Cell biology, Killer Cells, Natural, Receptors, Lysosphingolipid, medicine.anatomical_structure, MESH: T-Lymphocytes, chemistry, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Sphingosine, Lysophospholipids, 030215 immunology, Homing (hematopoietic)
Abstract

International audience; Consistent with their function in immune surveillance, natural killer (NK) cells are distributed throughout lymphoid and nonlymphoid tissues. However, the mechanisms governing the steady-state trafficking of NK cells remain unknown. The lysophospholipid sphingosine 1-phosphate (S1P), by binding to its receptor S1P1, regulates the recirculation of T and B lymphocytes. In contrast, S1P5 is detected in the brain and regulates oligodendrocyte migration and survival in vitro. Here we show that S1P5 was also expressed in NK cells in mice and humans and that S1P5-deficient mice had aberrant NK cell homing during steady-state conditions. In addition, we found that S1P5 was required for the mobilization of NK cells to inflamed organs. Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P5.

Published
2007
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11. Role for furin in tumor necrosis factor alpha-induced activation of the matrix metalloproteinase/sphingolipid mitogenic pathway

Author

Anne Nègre-Salvayre, Béatrice Bocquet, Yusuf A. Hannun, Shigeyoshi Itohara, Robert Salvayre, Nathalie Augé, Edwige Tellier, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), RIKEN Center for Brain Science [Wako] (RIKEN CBS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Department of Biochemistry and Molecular Biology, Medical University of South Carolina [Charleston] (MUSC), Simon, Marie Francoise, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), RIKEN Brain Research Institute, Riken Brain Research Institute, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
MESH: Signal Transduction, Small interfering RNA, MESH: Monensin, [SDV]Life Sciences [q-bio], MESH: Rabbits, MESH: Furin, Matrix metalloproteinase, MESH: Sphingomyelins, Mice, chemistry.chemical_compound, MESH: Matrix Metalloproteinase 14, 0302 clinical medicine, Sphingosine, MESH: Animals, Furin, 0303 health sciences, Kinase, MESH: Myocytes, Smooth Muscle, Articles, MESH: Mitogens, Sphingomyelins, Cell biology, Sphingomyelin Phosphodiesterase, MESH: trans-Golgi Network, 030220 oncology & carcinogenesis, embryonic structures, Matrix Metalloproteinase 2, Tumor necrosis factor alpha, Rabbits, MESH: Sphingosine, Batimastat, Signal Transduction, trans-Golgi Network, MESH: Enzyme Activation, Myocytes, Smooth Muscle, Biology, Ceramides, Models, Biological, MESH: Lysophospholipids, MESH: Sphingolipids, 03 medical and health sciences, MESH: Cell Proliferation, Matrix Metalloproteinase 14, Animals, Humans, Monensin, Molecular Biology, MESH: Mice, Cell Proliferation, 030304 developmental biology, Sphingolipids, Brefeldin A, MESH: Humans, MESH: Brefeldin A, Tumor Necrosis Factor-alpha, MESH: Models, Biological, Cell Biology, Fibroblasts, Sphingolipid, MESH: Ceramides, Enzyme Activation, MESH: Matrix Metalloproteinase 2, chemistry, MESH: Sphingomyelin Phosphodiesterase, MESH: Fibroblasts, MESH: Tumor Necrosis Factor-alpha, biology.protein, Lysophospholipids, Mitogens
Abstract

International audience; Neutral sphingomyelinase (nSMase), the initial enzyme of the sphingolipid signaling pathway, is thought to play a key role in cellular responses to tumor necrosis factor alpha (TNF-alpha), such as inflammation, proliferation, and apoptosis. The mechanism of TNF-alpha-induced nSMase activation is only partly understood. Using biochemical, molecular, and pharmacological approaches, we found that nSMase activation triggered by TNF-alpha is required for TNF-alpha-induced proliferation and in turn requires a proteolytic cascade involving furin, membrane type 1 matrix metalloproteinase (MT1-MMP), and MMP2, and leading finally to extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and DNA synthesis, in smooth muscle cells (SMC) and fibroblasts. Pharmacological and molecular inhibitors of MMPs (batimastat), furin (alpha1-PDX inhibitor-transfected SMC), MT1-MMP (SMC overexpressing a catalytically inactive MT1-MMP), MMP2 (fibroblasts from MMP2(-/-) mice), and small interfering RNA (siRNA) strategies (siRNAs targeting furin, MT1-MMP, MMP2, and nSMase) resulted in near-complete inhibition of the activation of nSMase, sphingosine kinase-1, and ERK1/2 and of subsequent DNA synthesis. Exogenous MT1-MMP activated nSMase and SMC proliferation in normal but not in MMP2(-/-) fibroblasts, whereas exogenous MMP2 was active on both normal and MMP2(-/-) fibroblasts. Altogether these findings highlight a pivotal role for furin, MT1-MMP, and MMP2 in TNF-alpha-induced sphingolipid signaling, and they identify this system as a possible target to inhibit SMC proliferation in vascular diseases.

Published
2007
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12. Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis

Author

Audrey Dayon, Oxana Kunduzova, Denis Calise, Angelo Parini, Nathalie Leducq, Olivier Cuvillier, Isabelle Seif, Marie-Hélène Seguelas, Dimitri Pchejetski, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Pharmacologie Moleculaire et Physiopathologie Renale, Service de Microchirurgie, Université Toulouse III - Paul Sabatier (UT3), Cardiovascular and Thrombosis Department, Sanofi-Aventis, Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Microchirurgie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise

Subjects
Physiology, Drug Resistance, MESH: Myocytes, Cardiac, Apoptosis, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Mice, Knockout, Mitochondria, Heart, MESH: Down-Regulation, Rats, Sprague-Dawley, Mice, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, MESH: Oxidants, MESH: Up-Regulation, Myocytes, Cardiac, MESH: Animals, Cells, Cultured, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, MESH: Oxidative Stress, biology, MESH: Reactive Oxygen Species, Oxidants, MESH: Myocardial Reperfusion Injury, Up-Regulation, Cell biology, Phosphotransferases (Alcohol Group Acceptor), Sphingosine kinase 1, MESH: Drug Resistance, MESH: Hydrogen Peroxide, MESH: Mitochondria, Heart, Monoamine oxidase A, MESH: Sphingosine, Cardiology and Cardiovascular Medicine, MESH: Cells, Cultured, Serotonin, Ceramide, medicine.medical_specialty, MESH: Rats, Down-Regulation, Myocardial Reperfusion Injury, Ceramides, MESH: Monoamine Oxidase, MESH: Lysophospholipids, MESH: Sphingolipids, 03 medical and health sciences, Internal medicine, medicine, Animals, Monoamine Oxidase, MESH: Mice, 030304 developmental biology, Sphingolipids, Reactive oxygen species, MESH: Apoptosis, Hydrogen Peroxide, Lipid signaling, Sphingolipid, MESH: Phosphotransferases (Alcohol Group Acceptor), MESH: Ceramides, Rats, Oxidative Stress, Endocrinology, chemistry, biology.protein, MESH: Serotonin, Lysophospholipids, Reactive Oxygen Species, Oxidative stress
Abstract

The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species–dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A– and reactive oxygen species–dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A–dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C 2 -ceramide or H 2 O 2 . In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H 2 O 2 -induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed significant upregulation of ceramide and inhibition of SphK1. It is noteworthy that SphK1 inhibition, ceramide accumulation, and concomitantly infarct size and cardiomyocyte apoptosis were significantly decreased in MAO-A–deficient animals. In conclusion, we show for the first time that the upregulation of ceramide/sphingosine 1-phosphate ratio is a critical event in MAO-A–mediated cardiac cell apoptosis. In addition, we provide the first evidence linking generation of reactive oxygen species with SphK1 inhibition. Finally, we propose sphingolipid metabolites as key mediators of postischemic/reperfusion cardiac injury.

Published
2007
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13. Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision?

Author

Thierry Levade, Patrice Codogno, Grégory Lavieu, Joëlle Botti, Giusy Sala, Francesca Scarlatti, Riccardo Ghidoni, Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Biochemistry and Molecular Biology, San Paolo Medical School, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations des réactions immunitaires et inflammatoires, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Codogno, Patrice, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cell Death, Programmed cell death, Ceramide, Cell Survival, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell fate determination, Ceramides, Models, Biological, MESH: Lysophospholipids, MESH: Sphingolipids, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Sphingosine, Autophagy, Humans, MESH: Autophagy, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, Sphingolipids, MESH: Humans, Cell Death, Mechanism (biology), MESH: Models, Biological, Cell Biology, Sphingolipid, MESH: Ceramides, Cell biology, chemistry, MESH: Cell Survival, 030220 oncology & carcinogenesis, Second messenger system, lipids (amino acids, peptides, and proteins), Lysophospholipids, MESH: Sphingosine
Abstract

Sphingolipids are major constituents of biological membrane and some of them behave as second messengers involved in the cell fate decision. Ceramide and sphingosine 1-phosphate (S1P) constitute a rheostat system in which ceramide promotes cell death and S1P increases cell survival. We have shown that both sphingolipids are able to trigger autophagy with opposing outcomes on cell survival. Here we discuss and speculate on the diverging functions of the autophagic pathways induced by ceramide and S1P, respectively.

Published
2007

14. PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: involvement of c-Fos in PACAP-induced Bcl-2 expression

Author

Cecile Fisch, Xavier Xifró, Jean‐François Lebigot, Nicolas Aubert, Bruno J. Gonzalez, Alain Fournier, Hubert Vaudry, Stephane De Jouffrey, José Rodríguez-Alvarez, David Vaudry, Anthony Falluel-Morel, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIT (CIT), CIT, Laboratory of Biochemistry and Molecular Biology, Neuroscience Institute-Autonomous University of Barcelona, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This work was supported by INSERM (U413), the CIT, a France-Quebec exchange program (INSERM-FRSQ), the Regional Platform for Cell Imaging, and the Conseil Régional de Haute-Normandie

Subjects
Proto-Oncogene Proteins c-jun, MESH: Neurons, Apoptosis, Biochemistry, c-Fos, MESH: Animals, Newborn, MESH: Down-Regulation, MESH: Dose-Response Relationship, Drug, 0302 clinical medicine, Sphingosine, Gene expression, Phosphoprotein Phosphatases, MESH: Animals, Protein Phosphatase 2, Enzyme Inhibitors, Phosphorylation, Cells, Cultured, Neurons, 0303 health sciences, Kinase, MESH: Proto-Oncogene Proteins c-fos, MESH: Protein Phosphatase 2, MESH: Gene Expression Regulation, MESH: Transcription Factor AP-1, 3. Good health, DNA-Binding Proteins, Proto-Oncogene Proteins c-bcl-2, MESH: Cell Survival, MESH: Enzyme Inhibitors, Mitogen-activated protein kinase, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Sphingosine, Proto-Oncogene Proteins c-fos, hormones, hormone substitutes, and hormone antagonists, MESH: Cells, Cultured, Transcriptional Activation, endocrine system, MESH: Rats, Cell Survival, MAP Kinase Signaling System, Down-Regulation, Adenylate kinase, Biology, Cerebellar Cortex, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Phosphoprotein Phosphatases, Animals, Rats, Wistar, Protein kinase A, 030304 developmental biology, MESH: Cerebellar Cortex, Dose-Response Relationship, Drug, MESH: Phosphorylation, MESH: Proto-Oncogene Proteins c-jun, MESH: MAP Kinase Signaling System, MESH: Apoptosis, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Protein phosphatase 2, MESH: Rats, Wistar, Molecular biology, Rats, Transcription Factor AP-1, Animals, Newborn, Gene Expression Regulation, MESH: Proto-Oncogene Proteins c-bcl-2, biology.protein, MESH: Transcriptional Activation, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract

International audience; The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits C2-ceramide-induced cell death through blockade of the mitochondrial apoptotic pathway in rat cerebellar granule neurones. However, the gene induction processes and transcription factors involved in the anti-apoptotic effect of PACAP remain unknown. Here, we show that PACAP and C2-ceramide activate activator protein-1 (AP-1) DNA binding in a dose- and time-dependent manner, but generate different AP-1 dimers. Thus, PACAP increased the proportion of c-Fos and Jun D while C2-ceramide increased c-Jun and reduced c-Fos in AP-1 complexes. In addition, PACAP strongly activated c-Fos gene expression while C2-ceramide markedly increased c-Jun phosphorylation. The effect of PACAP on c-Fos expression was blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor, U0126, while phosphorylation of c-Jun induced by C2-ceramide was abrogated by the protein phosphatase 2A (PP2A) inhibitor, okadaic acid. Transfection of immature granule cells with c-Fos siRNA, which strongly reduced basal and PACAP-stimulated levels of the protein, totally prevented the stimulatory effect of PACAP on Bcl-2 expression. The present study demonstrates that AP-1 complexes containing c-Fos mediate the effect of PACAP on Bcl-2 gene expression in cerebellar granule neurones. Our data also indicate that different AP-1 dimers are associated with the pro-apoptotic effect of C2-ceramide and the anti-apoptotic effect of PACAP.

Published
2006
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15. Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells

Author

Falluel-Morel, Anthony, Aubert, Nicolas, Vaudry, David, Basille, Magali, Fontaine, Marc, Fournier, Alain, Vaudry, Hubert, Gonzalez, Bruno J, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Defense Proteins in Immune and Inflammatory Responses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Faculty of Medicine and Pharmacy-European Institute for Peptide Research-Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This research was supported by an INSERM Grant (U413) and an IREB Grant (2001/22). AFM is recipient of a fellowship from the Conseil Re ́gional de Haute-Normandie (LARC-Neuroscience net- work). NA is a recipient of a fellowship from the Conseil Régional de Haute-Normandie and the CIT-IFM Recherche.

Subjects
MESH: Signal Transduction, Time Factors, MAP Kinase Kinase 4, MESH: Drug Interactions, MESH: Neurons, Fluorescent Antibody Technique, MESH: Neurotransmitter Agents, MESH: Neuropeptides, MESH: Caspase 9, MESH: Animals, Newborn, MESH: Dose-Response Relationship, Drug, Membrane Potentials, Mice, Cytosol, MESH: Cytosol, Sphingosine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Cerebellum, MESH: Caspase 3, MESH: Animals, Drug Interactions, Enzyme Inhibitors, MESH: Fluorescent Antibody Technique, Cells, Cultured, bcl-2-Associated X Protein, Neurons, Neurotransmitter Agents, Caspase 3, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Cytochromes c, MESH: Cytochromes c, Carbocyanines, MESH: Gene Expression Regulation, Caspase 9, Mitochondria, ERK, Proto-Oncogene Proteins c-bcl-2, MESH: Enzyme Inhibitors, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Caspases, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Carbocyanines, MESH: Sphingosine, Mitogen-Activated Protein Kinases, hormones, hormone substitutes, and hormone antagonists, MESH: MAP Kinase Kinase 4, MESH: Cells, Cultured, Signal Transduction, endocrine system, MESH: Rats, MESH: Mitochondria, Blotting, Western, Models, Neurological, MESH: Mitogen-Activated Protein Kinase Kinases, mitochondrial apoptotic pathway, MESH: Models, Neurological, MESH: Intracellular Signaling Peptides and Proteins, MESH: Membrane Potentials, MESH: Blotting, Western, Animals, Bcl-2, MESH: bcl-2-Associated X Protein, Nerve Growth Factors, RNA, Messenger, Rats, Wistar, MESH: Mice, MESH: RNA, Messenger, Mitogen-Activated Protein Kinase Kinases, MESH: Caspases, Dose-Response Relationship, Drug, MESH: Nerve Growth Factors, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Time Factors, Neuropeptides, JNK Mitogen-Activated Protein Kinases, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Rats, Wistar, MESH: Mitogen-Activated Protein Kinases, MESH: Cerebellum, Rats, MESH: Proto-Oncogene Proteins c-bcl-2, Animals, Newborn, Gene Expression Regulation, Bax, Benzimidazoles, JNK, MESH: Benzimidazoles
Abstract

International audience; The sphingomyelin-derived messenger ceramides provoke neuronal apoptosis through caspase-3 activation, while the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neuronal survival and inhibits caspase-3 activity. However, the mechanisms leading to the opposite regulation of caspase-3 by C2-ceramide and PACAP are currently unknown. Here, we show that PACAP prevents C2-ceramide-induced inhibition of mitochondrial potential and C2-ceramide-evoked cytochrome c release. C2-ceramide stimulated Bax expression, but had no effect on Bcl-2, while PACAP abrogated the action of C2-ceramide on Bax and stimulated Bcl-2 expression. The effects of C2-ceramide and PACAP on Bax and Bcl-2 were blocked, respectively, by the JNK inhibitor L-JNKI1 and the MEK inhibitor U0126. L-JNKI1 prevented the alteration of mitochondria induced by C2-ceramide while U0126 suppressed the protective effect of PACAP against the deleterious action of C2-ceramide on mitochondrial potential. Moreover, L-JNKI1 inhibited the stimulatory effect of C2-ceramide on caspase-9 and -3 and prevented C2-ceramide-induced cell death. U0126 blocked PACAP-induced Bcl-2 expression, abrogated the inhibitory effect of PACAP on ceramide-induced caspase-9 activity, and promoted granule cell death. The present study reveals that C2-ceramide and PACAP exert opposite effects on Bax and Bcl-2 through, respectively, JNK- and ERK-dependent mechanisms. These data indicate that the mitochondrial pathway plays a pivotal role in the pro- and anti-apoptotic effects of C2-ceramide and PACAP.

Published
2004
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16. EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway

Author

Christophe Deroanne, Valérie Vouret-Craviari, Jacques Pouysségur, Bingcheng Wang, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Rammelkamp Center for Research (R421), and Case Western Reserve University [Cleveland]

Subjects
MESH: Signal Transduction, Integrins, RHOA, MESH: rac GTP-Binding Proteins, Muscle, Smooth, Vascular, PAK1, Cell Movement, Sphingosine, MESH: Animals, Enzyme Inhibitors, p21-activated kinases, cdc42 GTP-Binding Protein, MESH: Cell Movement, Cells, Cultured, Feedback, Physiological, 0303 health sciences, biology, 030302 biochemistry & molecular biology, MESH: Integrins, Ephrin-A1, MESH: Muscle, Smooth, Vascular, Cell biology, rac GTP-Binding Proteins, MESH: Enzyme Inhibitors, RNA Interference, MESH: Sphingosine, Lamellipodium, MESH: Neovascularization, Physiologic, MESH: Cells, Cultured, Signal Transduction, MESH: Ephrin-A1, MESH: p21-Activated Kinases, MESH: rhoA GTP-Binding Protein, MESH: Rats, MESH: RNA Interference, Neovascularization, Physiologic, [SDV.CAN]Life Sciences [q-bio]/Cancer, RAC1, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH: Cell Adhesion, MESH: Lysophospholipids, 03 medical and health sciences, Cell Adhesion, Ephrin, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: cdc42 GTP-Binding Protein, MESH: Feedback, Biochemical, Erythropoietin-producing hepatocellular (Eph) receptor, Cell Biology, Rats, p21-Activated Kinases, Rho kinase inhibitor, biology.protein, Lysophospholipids, rhoA GTP-Binding Protein
Abstract

International audience; Interactions between the Eph receptor tyrosine kinase and ephrin ligands transduce short-range signals regulating axon pathfinding, development of the cardiovascular system, as well as migration and spreading of neuronal and non-neuronal cells. Some of these effects are believed to be mediated by alterations in actin dynamics. The members of the small Rho GTPase family elicit various effects on actin structures and are probably involved in Eph receptor-induced actin modulation. EphrinA1 is proposed to contribute to angiogenesis as it is strongly expressed at sites of neovascularization. Moreover, angiogenic factors induce the expression of ephrinA1 in endothelial cells. In this study, using rat vascular smooth muscle cells (VSMCs), we investigated the contribution of the small Rho GTPases in ephrinA1-induced integrin inactivation. EphrinA1 did not significantly affect early adhesion of VSMCs on purified laminin or fibronectin, but strongly impaired cell spreading. The Rho kinase inhibitor Y-27632 partly reversed the ephrinA1 effect, suggesting involvement of Rho in this model. However, inhibition of RhoA synthesis with short interfering (si)RNA had a modest effect, suggesting that RhoA plays a limited role in ephrinA1-mediated inhibition of spreading in VSMCs. The ephrinA1-mediated morphological alterations correlated with inhibition of Rac1 and p21-activated kinase 1 (PAK1) activity, and were antagonized by the expression of a constitutively active Rac mutant. Moreover, repression of Rac1 synthesis with siRNA amplifies the ephrinA1-induced inhibition of spreading. Finally, sphingosine-1-phosphate (S1P), a lipid mediator known to inhibit Rac activation in VSMCs amplifies the ephrinA1 effect. In conclusion, our results emphasize the role of the Rac/PAK pathway in ephrinA1-mediated inhibition of spreading. In this way, ephrinA1, alone or in synergy with S1P, can participate in blood vessel destabilization, a prerequisite for angiogenesis.

Published
2003

17. Identification of genes involved in ceramide-dependent neuronal apoptosis using cDNA arrays

Author

Decraene, C., Brugg, B., Ruberg, M., Eveno, E., Matingou, C., Tahi, F., Jean Mariani, Auffray, C., Pietu, G., Genexpress, Centre National de la Recherche Scientifique (CNRS), Service de Génomique Fonctionnelle, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurologie Expérimentale et Thérapeutique, IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Évry-Val-d'Essonne (UEVE), This work was supported by the CNRS and grants from European Union to J.M. (TMR projet Neuril) and BIOMED2 programs (EURO-IMAGE Consortium, BMH4-CT-97-2284) to C.A. C.M. was supported by Genome Express and C.D. acknowledges fellowships from the Fédération Française des Groupements Parkinsoniens (FFGP) and the Association pour la Recherche sur le Cancer (ARC)., and Maylin, Françoise

Subjects
MESH: Signal Transduction, MESH: Cell Differentiation, MESH: Rats, MESH: Neurons, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, PC12 Cells, MESH: Nucleic Acid Hybridization, MESH: Gene Expression Profiling, Sphingosine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, MESH: PC12 Cells, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Oligonucleotide Array Sequence Analysis, Neurons, Research, Gene Expression Profiling, MESH: Apoptosis, Nucleic Acid Hybridization, Cell Differentiation, MESH: Genes, Rats, Genes, MESH: Oligonucleotide Array Sequence Analysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Sphingosine, Signal Transduction
Abstract

A cell-culture model was used to establish a profile of gene expression during the effector phase of ceramide-mediated cell death. Of the 239 genes that met the criteria for differential hybridization, 10 correspond to genes previously involved in C2-ceramide or TNF-α signaling pathways and 20 in neuronal disorders, oncogenesis or more broadly in the regulation of proliferation., Background Ceramide is important in many cell responses, such as proliferation, differentiation, growth arrest and apoptosis. Elevated ceramide levels have been shown to induce apoptosis in primary neuronal cultures and neuronally differentiated PC 12 cells. Results To investigate gene expression during ceramide-dependent apoptosis, we carried out a global study of gene expression in neuronally differentiated PC 12 cells treated with C2-ceramide using an array of 9,120 cDNA clones. Although the criteria adopted for differential hybridization were stringent, modulation of expression of 239 genes was identified during the effector phase of C2-ceramide-induced cell death. We have made an attempt at classifying these genes on the basis of their putative functions, first with respect to known effects of ceramide or ceramide-mediated transduction systems, and then with respect to regulation of cell growth and apoptosis. Conclusions Our cell-culture model has enabled us to establish a profile of gene expression during the effector phase of ceramide-mediated cell death. Of the 239 genes that met the criteria for differential hybridization, 10 correspond to genes previously involved in C2-ceramide or TNF-α signaling pathways and 20 in neuronal disorders, oncogenesis or more broadly in the regulation of proliferation. The remaining 209 genes, with or without known functions, constitute a pool of genes potentially implicated in the regulation of neuronal cell death.

Published
2002

18. Sphingoid base signaling via Pkh kinases is required for endocytosis in yeast

Author

Sylvie Friant, Michael N. Hall, Ruben Lombardi, Howard Riezman, Tobias Schmelzle, Génétique moléculaire, génomique, microbiologie (GMGM), and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Time Factors, Phalloidine, MESH: Microscopy, Fluorescence, MESH: Dose-Response Relationship, Drug, MESH: Genotype, MESH: Saccharomyces cerevisiae Proteins, Sphingosine, MESH: Precipitin Tests, Phosphorylation, Internalization, Cytoskeleton, media_common, Kinase, General Neuroscience, MESH: Saccharomyces cerevisiae, Endocytosis, Cell biology, Biochemistry, MESH: Endocytosis, MESH: Sphingosine, Signal transduction, MESH: Phalloidine, Plasmids, Signal Transduction, MESH: Mutation, Saccharomyces cerevisiae Proteins, Genotype, media_common.quotation_subject, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Saccharomyces cerevisiae, MESH: Rhodamines, Biology, Protein Serine-Threonine Kinases, MESH: Actins, MESH: Protein-Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Article, 3-Phosphoinositide-Dependent Protein Kinases, MESH: Plasmids, MESH: Cytoskeleton, MESH: Protein Kinases, Molecular Biology, Eisosome, Protein-Serine-Threonine Kinases, MESH: Phosphorylation, General Immunology and Microbiology, Dose-Response Relationship, Drug, Rhodamines, MESH: Time Factors, Actin cytoskeleton, Precipitin Tests, Actins, Microscopy, Fluorescence, Mutation, Protein Kinases
Abstract

In yeast, sphingoid base synthesis is required for the internalization step of endocytosis and organization of the actin cytoskeleton. We show that overexpression of either one of the two kinases Pkh1p or Pkh2p, that are homologous to mammalian 3-phosphoinositide-dependent kinase-1 (PDK1), can specifically suppress the sphingoid base synthesis requirement for endocytosis. Pkh1p and Pkh2p have an overlapping function because only a mutant with impaired function of both kinases is defective for endocytosis. Pkh1/2p kinases are activated in vitro by nanomolar concentrations of sphingoid base. These results suggest that Pkh1/2p kinases are part of a sphingoid base-mediated signaling pathway that is required for the internalization step of endocytosis. The Pkc1p kinase that is phosphorylated by Pkh1/2p kinases and plays a role in endocytosis was identified as one of the downstream effectors of this signaling cascade.

Published
2001
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19. Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae

Author

Howard Riezman, Kouichi Funato, Sylvie Friant, Bettina Zanolari, Christine Sütterlin, Brian J. Stevenson, Génétique moléculaire, génomique, microbiologie (GMGM), and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ceramide, MESH: Mutation, Saccharomyces cerevisiae Proteins, media_common.quotation_subject, Endocytic cycle, Saccharomyces cerevisiae, Serine C-Palmitoyltransferase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Acyltransferases, Endocytosis, Ceramides, General Biochemistry, Genetics and Molecular Biology, MESH: Sphingolipids, chemistry.chemical_compound, MESH: Saccharomyces cerevisiae Proteins, Sphingosine, Internalization, Molecular Biology, Eisosome, media_common, MESH: Serine C-Palmitoyltransferase, Sphingolipids, General Immunology and Microbiology, General Neuroscience, Articles, biology.organism_classification, Sphingolipid, MESH: Ceramides, MESH: Saccharomyces cerevisiae, Cell biology, chemistry, Biochemistry, MESH: Endocytosis, Mutation, MESH: Sphingosine, Acyltransferases
Abstract

The internalization step of endocytosis in yeast requires actin and sterols for maximum efficiency. In addition, many receptors and plasma membrane proteins must be phosphorylated and ubiquitylated prior to internalization. The Saccharomyces cerevisiae end8-1 mutant is allelic to lcb1, a mutant defective in the first step of sphingoid base synthesis. Upon arrest of sphingoid base synthesis a rapid block in endocytosis is seen. This block can be overcome by exogenous sphingoid base. Under conditions where endogenous sphingosine base synthesis was blocked and exogenous sphingoid bases could not be converted to phosphorylated sphingoid bases or to ceramide, sphingoid bases could still suppress the endocytic defect. Therefore, the required lipid is most likely a sphingoid base. Interestingly, sphingoid base synthesis is required for proper actin organization, but is not required for receptor phosphorylation. This is the first case of a physiological role for sphingoid base synthesis, other than as a precursor for ceramide or phosphorylated sphingoid base synthesis.

Published
2000
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20. Intracellular pH and intracellular free calcium responses to protein kinase C activators and inhibitors in Xenopus eggs

Author

Nathalie Grandin, Michel Charbonneau, Laboratoire d'Innovation pour les Technologies des Energies Nouvelles et les nanomatériaux (LITEN), Institut National de L'Energie Solaire (INES), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Intracellular Fluid, MESH: Hydrogen-Ion Concentration, Intracellular pH, [SDV]Life Sciences [q-bio], Xenopus, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Exocytosis, MESH: Oocytes, 03 medical and health sciences, Xenopus laevis, 0302 clinical medicine, Alkaloids, MESH: Alkaloids, MESH: Xenopus laevis, Sphingosine, Animals, MESH: Animals, Molecular Biology, Protein kinase C, Protein Kinase C, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Cortical granule exocytosis, MESH: Intracellular Fluid, Oocyte activation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hydrogen-Ion Concentration, biology.organism_classification, Staurosporine, MESH: Protein Kinase C, Cell biology, Biochemistry, MESH: Calcium, MESH: Staurosporine, Oocytes, Calcium, Female, MESH: Sphingosine, Cell activation, MESH: Female, Intracellular, Developmental Biology
Abstract

Cell activation during fertilization of the egg of Xenopus laevis is accompanied by various metabolic changes, including a permanent increase in intracellular pH (pHi) and a transient increase in intracellular free calcium activity ([Ca2+]1,). Recently, it has been proposed that protein kinase C (PKC) is an integral component of the Xenopus fertilization pathway (Bement and Capeo, J. Cell Biol. 108, 885-892, 1989). Indeed, activators of PKC trigger cortical granule exocytosis and cortical contraction, two events of egg activation, without, however, releasing the cell cycle arrest (blocked in second metaphase of meiosis). In the egg of Xenopus, exocytosis as well as cell cycle reinitiation are supposed to be triggered by the intracellular Ca2+ transient. We report here that PKC activators do not induce the intracellular Ca2+ transient, or the activation-associated increase in pHi. These results suggest that the ionic responses to egg activation in Xenopus do not appear to depend on the activation of PKC. In addition, in eggs already pretreated with phorbol esters, those artificial activators that act by releasing Ca2+ intracellularly, triggered a diminished increase in pHi. Finally, sphingosine and staurosporine, two potent inhibitors of PKC, were found to trigger egg activation, suggesting that a decrease in PKC activity might be an essential event in the release of the metaphase block, in agreement with recent findings on the release of the prophase block in Xenopus oocytes (Varnold and Smith, Development 109, 597–604, 1990).

Published
1991

21. Increased protein kinase or decreased PP2A activity bypasses sphingoid base requirement in endocytosis

Author

Bettina Zanolari, Howard Riezman, Sylvie Friant, Génétique moléculaire, génomique, microbiologie (GMGM), and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Mutation, MESH: Casein Kinases, Serine C-Palmitoyltransferase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, macromolecular substances, Saccharomyces cerevisiae, MESH: Acyltransferases, Biology, MESH: Actins, Endocytosis, General Biochemistry, Genetics and Molecular Biology, Actin cytoskeleton organization, Sphingosine, MESH: Cytoskeleton, Phosphoprotein Phosphatases, Protein phosphorylation, Protein Phosphatase 2, Cytoskeleton, MESH: Protein Kinases, Molecular Biology, Actin, Protein Kinase C, MESH: Serine C-Palmitoyltransferase, General Immunology and Microbiology, Kinase, General Neuroscience, Articles, Actin cytoskeleton, MESH: Protein Kinase C, MESH: Saccharomyces cerevisiae, Actins, Cell biology, Biochemistry, MESH: Endocytosis, Mutation, MESH: Phosphoprotein Phosphatase, MESH: Sphingosine, Casein kinases, Casein Kinases, Protein Kinases, Acyltransferases, Signal Transduction
Abstract

Lipids have been implicated in signal transduction and in several stages of membrane trafficking, but these two functions have not been functionally linked. In yeast, sphingoid base synthesis is required for the internalization step of endocytosis and organization of the actin cytoskeleton. We show that inactivation of a protein phosphatase 2A (PP2A) or overexpression of one of two kinases, Yck2p or Pkc1p, can specifically suppress the sphingoid base synthesis requirement for endocytosis. The two kinases have an overlapping function because only a mutant with impaired function of both kinases is defective in endocytosis. An ultimate target of sphingoid base synthesis may be the actin cytoskeleton, because overexpression of the kinases and inactivation of PP2A substantially corrected the actin defect due to the absence of sphingoid base. These results suggest that sphingoid base controls protein phosphorylation, perhaps by activating a signal transduction pathway that is required for endocytosis and proper actin cytoskeleton organization in yeast.

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