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1. Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9

Author

Patrick Mehlen, Chantal Thibert, Rémy Sadoul, Joanna Fombonne, Catherine Guix, Pierre-Antoine Bissey, Puisieux, Alain, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 2, Neurodégénérescence et plasticité, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by institutional grants from the Ligue Contre le Cancer, INCA, ANR, and IP ApoSys., Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Grenoble Institut des Neurosciences ( GIN ), and Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
MESH : Cell Line, endocrine system diseases, Apoptosis, NEDD4, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Dependence receptor, MESH : Ubiquitination, 0302 clinical medicine, Ubiquitin, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Caspase 3, MESH : Caspase 3, ComputingMilieux_MISCELLANEOUS, Caspase-9, 0303 health sciences, Multidisciplinary, biology, Caspase 3, MESH: Real-Time Polymerase Chain Reaction, Signal transducing adaptor protein, Biological Sciences, MESH : Mutagenesis, Site-Directed, Ubiquitin ligase, MESH: Mutagenesis, Site-Directed, 030220 oncology & carcinogenesis, Patched, MESH : Real-Time Polymerase Chain Reaction, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Real-Time Polymerase Chain Reaction, MESH: Two-Hybrid System Techniques, Cell Line, 03 medical and health sciences, Two-Hybrid System Techniques, signalisation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, posttranslational modification, MESH: Humans, MESH: Apoptosis, MESH : Humans, Ubiquitination, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, protease, MESH: Cell Line, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, MESH : Two-Hybrid System Techniques, Mutagenesis, Site-Directed, biology.protein, Cancer research, MESH: Ubiquitination, MESH : Apoptosis
Abstract

International audience; Patched (Ptc), the main receptor for Sonic Hedgehog, is a tumor suppressor. Ptc has been shown to be a dependence receptor, and as such triggers apoptosis in the absence of its ligand. This apoptosis induction occurs through the recruitment by the Ptc intracellular domain of a caspase-activating complex, which includes the adaptor proteins DRAL and TUCAN, and the apical caspase-9. We show here that this caspase-activating complex also includes the E3 ubiquitin ligase NEDD4. We demonstrate that Ptc-mediated apoptosis and Ptc-induced caspase-9 activation require NEDD4. We show that Ptc, but not Bax, the prototypical inducer of the intrinsic cell-death pathway, triggers polyubiquitination of caspase-9. Moreover, a caspase-9 mutant that could not be ubiquitinated failed to mediate Ptc-induced apoptosis. Taken together, these data support the view that the Ptc dependence receptor specifically allows the activation of caspase-9 via its ubiquitination, which occurs via the recruitment by Ptc of NEDD4.

Published
2012
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2. Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy

Author

Anastasia R. Goloudina, Elena Y. Kochetkova, Marc Bardou, Arlette Hammann, Oleg N. Demidov, Sarah Richaud, Carmen Garrido, Olga A. Fedorova, Nickolai A. Barlev, Burhan Uyanik, V Clausse, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institute of Cytology of the Russian Academy of Science (St. Petersburg), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Fondation ARC, laboratoire d'excellence ARC, La Ligue Contre le Cancer CCIR-GE (14-15-00636 ), fondation scientifique russe, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER

Subjects
Wip1, Apoptosis, Cell Cycle Proteins, Pharmacology, MESH: G2 Phase Cell Cycle Checkpoints, Histones, MESH : Phosphorylation, Mice, MESH : Cell Cycle Proteins, MESH: Animals, MESH: Tumor Suppressor Protein p53, MESH: Histones, Kinase, Tp53 mutations, MESH : Mice, Transgenic, 3. Good health, Protein Phosphatase 2C, Survival Rate, MESH : Antineoplastic Agents, H2ax phosphorylation, P53 activation, MESH: Protein Phosphatase 2C, RNA Interference, MESH : Colorectal Neoplasms, MESH : Carrier Proteins, Histone H2ax, MESH: Mitochondria, Immunology, Human fibroblasts, MESH: Carrier Proteins, Antineoplastic Agents, MESH: Protein-Tyrosine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH : Cisplatin, 03 medical and health sciences, MESH: Cell Cycle Proteins, Genotoxic stress, MESH : Protein-Tyrosine Kinases, Humans, MESH : Histones, Anticancer Therapy, MESH: DNA Damage, Cisplatin, MESH: Humans, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Humans, MESH : Nuclear Proteins, 030104 developmental biology, Cancer cell, MESH: Antineoplastic Agents, Carrier Proteins, MESH: Nuclear Proteins, MESH : Apoptosis, Dna-damage response, 0301 basic medicine, Cancer Research, MESH: Caspase 3, MESH : Caspase 3, Phosphorylation, Cytotoxicity, MESH : DNA Damage, Sensitization, medicine.diagnostic_test, Caspase 3, Nuclear Proteins, Protein-Tyrosine Kinases, MESH : Survival Rate, Mitochondria, G2 Phase Cell Cycle Checkpoints, Wee1, medicine.anatomical_structure, MESH : Protein Phosphatase 2C, Original Article, MESH : Mitochondria, Colorectal Neoplasms, medicine.drug, MESH : Protein-Serine-Threonine Kinases, MESH: Cell Line, Tumor, MESH: Survival Rate, MESH: Mice, Transgenic, MESH: RNA Interference, Phosphatase, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Protein Serine-Threonine Kinases, Flow cytometry, Cellular and Molecular Neuroscience, Cell Line, Tumor, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Cell Line, Tumor, MESH: Apoptosis, Cell Biology, MESH : Tumor Suppressor Protein p53, MESH: Cisplatin, Cancer research, biology.protein, MESH : Animals, MESH : G2 Phase Cell Cycle Checkpoints, MESH : RNA Interference, Tumor Suppressor Protein p53, MESH: Colorectal Neoplasms, DNA Damage
Abstract

Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1-dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination of Wee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy.

Published
2016
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3. CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension

Author

William Rostène, Julie Frugier, Françoise Baleux, David Godefroy, Isabelle Célérier, Serge Picaud, Françoise Brignole-Baudouin, Julie Degardin, Jeffrey K. Harrison, Christophe Baudouin, José Sahel, Alexandre Denoyer, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche des Cordeliers - Equipe 20 'ingénierie des connaissances en santé', Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Florida [Gainesville] (UF), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Chimie des biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), CIC Quinze-Vingts, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Laboratory of Toxicology, Faculty of Pharmaceutical and Biological Sciences, Université Paris Descartes - Paris 5 ( UPD5 ), Chimie des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), This work was supported by INSERM grants for AD, DG, JD, WR and CB, by a UPMC grant for IC and JF, and by an NIH grant for JKH (AI058256)., Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) ( APHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Godefroy, David

Subjects
Retinal degeneration, Male, Visual System, Ocular hypertension, Apoptosis, MESH : Cytoprotection, MESH : Receptors, CXCR4, MESH : Receptors, CXCR3, 0302 clinical medicine, MESH: Animals, lcsh:Science, MESH: Stress, Physiological, MESH : Glaucoma, 0303 health sciences, Neurodegeneration, Anatomy, MESH : Chemokine CXCL12, Sensory Systems, 3. Good health, [SDV] Life Sciences [q-bio], MESH : Retinal Degeneration, Medicine, MESH: Chemokine CXCL12, MESH: Glaucoma, medicine.medical_specialty, MESH: Enzyme Activation, Receptors, CXCR4, Receptors, CXCR3, MESH: Retinal Degeneration, Ocular Anatomy, Caspase 3, MESH: Receptors, CXCR4, MESH: Receptors, CXCR3, 03 medical and health sciences, Humans, Rats, Long-Evans, MESH: Vision, Ocular, Biology, Intraocular Pressure, MESH: Humans, [ SDV ] Life Sciences [q-bio], lcsh:R, MESH : Humans, Glaucoma, medicine.disease, MESH : Disease Models, Animal, eye diseases, Chemokine CXCL12, MESH: Cell Line, MESH: Ocular Hypertension, Enzyme Activation, MESH: Cytoprotection, Ophthalmology, Endocrinology, chemistry, 030221 ophthalmology & optometry, Rat, lcsh:Q, Ocular Hypertension, Trabecular meshwork, MESH: Disease Models, Animal, MESH : Apoptosis, Neuroscience, MESH : Cell Line, Intraocular pressure, Anatomy and Physiology, genetic structures, [SDV]Life Sciences [q-bio], MESH : Vision, Ocular, lcsh:Medicine, chemistry.chemical_compound, MESH: Caspase 3, Molecular Cell Biology, MESH : Caspase 3, MESH : Rats, Long-Evans, MESH : Intraocular Pressure, Multidisciplinary, Cell Death, MESH : Rats, Retinal Degeneration, Animal Models, MESH : Trabecular Meshwork, medicine.anatomical_structure, Research Article, MESH: Rats, MESH : Male, Cell Line, Model Organisms, MESH: Intraocular Pressure, MESH: Rats, Long-Evans, Stress, Physiological, Trabecular Meshwork, Ocular System, Internal medicine, medicine, MESH : Ocular Hypertension, Animals, MESH : Stress, Physiological, Vision, Ocular, 030304 developmental biology, MESH: Apoptosis, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Retinal, MESH: Male, Rats, MESH: Trabecular Meshwork, Disease Models, Animal, Cytoprotection, MESH : Animals, sense organs, MESH : Enzyme Activation
Abstract

International audience; Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.

Published
2012
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4. Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course

Author

Junhua Wang, Jing Li, Dominique A. Vuitton, Guodong Lü, Georges Mantion, Xiaomei Lu, Renyong Lin, Chuanshan Zhang, Hao Wen, Institut de Recherche en Communications et en Cybernétique de Nantes ( IRCCyN ), Mines Nantes ( Mines Nantes ) -École Centrale de Nantes ( ECN ) -Ecole Polytechnique de l'Université de Nantes ( Polytech Nantes ), Université de Nantes ( UN ) -Université de Nantes ( UN ) -PRES Université Nantes Angers Le Mans ( UNAM ) -Centre National de la Recherche Scientifique ( CNRS ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université de Franche-Comté ( UFC ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Xinjiang Medical University, Chinese Government, Institut de Recherche en Communications et en Cybernétique de Nantes (IRCCyN), Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Proteomics, MESH : Hepatocytes, MESH : Echinococcosis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, 0302 clinical medicine, Gene expression, MESH : Cell Proliferation, MESH: Animals, MESH : Antigens, Differentiation, MESH: In Situ Nick-End Labeling, lcsh:Science, MESH: Tumor Suppressor Protein p53, Regulation of gene expression, 0303 health sciences, MESH : Gene Expression Regulation, Intracellular Signaling Peptides and Proteins, 3. Good health, 030220 oncology & carcinogenesis, Disease Progression, Medicine, MESH: Disease Progression, MESH : Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p21, MESH : Cyclin-Dependent Kinase Inhibitor p21, MESH: Enzyme Activation, MESH : Cyclins, Caspase 3, MESH: Carrier Proteins, Gastroenterology and Hepatology, Echinococcus multilocularis, Microbiology, MESH: Cyclin-Dependent Kinase Inhibitor p21, 03 medical and health sciences, MESH: Echinococcosis, Cyclins, In Situ Nick-End Labeling, Biology, MESH: Echinococcus multilocularis, lcsh:R, MESH : Mitogen-Activated Protein Kinases, MESH : Disease Progression, Enzyme Activation, Apoptosis, Immunology, lcsh:Q, Parasitology, Carrier Proteins, MESH: Female, MESH: Liver, Necrosis, lcsh:Medicine, MESH : Models, Biological, MESH : Echinococcus multilocularis, Molecular Cell Biology, MESH: Caspase 3, MESH : Female, MESH : Caspase 3, Mice, Inbred BALB C, Multidisciplinary, biology, Animal Models, MESH: Gene Expression Regulation, medicine.anatomical_structure, Infectious Diseases, Liver, Hepatocyte, MESH: Antigens, Differentiation, MESH : In Situ Nick-End Labeling, Female, medicine.symptom, Mitogen-Activated Protein Kinases, Research Article, Neglected Tropical Diseases, MESH: Mice, Inbred BALB C, [SDV.CAN]Life Sciences [q-bio]/Cancer, Models, Biological, Andrology, Immune system, Model Organisms, Echinococcosis, Proliferating Cell Nuclear Antigen, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Cell Proliferation, MESH: Models, Biological, MESH : Liver, biology.organism_classification, MESH: Cyclins, Antigens, Differentiation, MESH: Mitogen-Activated Protein Kinases, MESH : Tumor Suppressor Protein p53, MESH: Proliferating Cell Nuclear Antigen, Gene Expression Regulation, MESH : Proliferating Cell Nuclear Antigen, Hepatocytes, MESH : Animals, Tumor Suppressor Protein p53, MESH : Enzyme Activation
Abstract

International audience; BACKGROUND: Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection. METHODOLOGY/PRINCIPAL FINDINGS: Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time. CONCLUSIONS: Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.

Published
2012
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5. c-mip down-regulates NF-κB activity and promotes apoptosis in podocytes

Author

Vincent Audard, Marina Candelier, Laure-Hélène Noël, André Pawlak, Georges Guellaen, Nabila Hamdaoui, Dominique Desvaux, Shao-yu Zhang, Philippe Lang, Djillali Sahali, Qingfeng Fan, Virginie Ory, Guellaen, Georges, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'histologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie et transplantation, Institut francilien de recheche en nephrologie et transplantation, IFRNT, This work was supported in part by an Avenir Program from INSERM, a grant from the French Kidney Foundation, Association pour l'Utilisation du Rein Artificiel (AURA), Assistance Publique des Hôpitaux de Paris (AP-HP, Programme hospitalier de recherche clinique) and a grant from the Fondation pour la Recherche Médicale (FRM)., Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Male, MESH : Cell Line, Nephrotic Syndrome, MESH: NF-kappa B, Apoptosis, Idiopathic Nephrotic Syndrome, MESH: Down-Regulation, Podocyte, MESH : Down-Regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Transcription Factor RelA, MESH: Caspase 3, MESH: Up-Regulation, MESH: Microscopy, Confocal, MESH : Caspase 3, MESH: Animals, MESH: In Situ Nick-End Labeling, MESH : Up-Regulation, 0303 health sciences, Microscopy, Confocal, Caspase 3, Podocytes, NF-kappa B, MESH : Adult, MESH : Podocytes, Pathophysiology, MESH : Mice, Transgenic, Up-Regulation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : NF-kappa B, MESH : In Situ Nick-End Labeling, MESH : Carrier Proteins, Adult, MESH: Mice, Transgenic, MESH : Nephrotic Syndrome, MESH : Male, Down-Regulation, Mice, Transgenic, MESH: Carrier Proteins, Biology, Cell Line, Pathology and Forensic Medicine, 03 medical and health sciences, In vivo, MESH : Mice, MESH: Podocytes, In Situ Nick-End Labeling, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Microscopy, Confocal, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Humans, MESH: Apoptosis, MESH : Transcription Factor RelA, MESH : Humans, Transcription Factor RelA, NF-κB, MESH: Adult, MESH: Male, MESH: Cell Line, Antiapoptotic protein, chemistry, Cancer research, MESH : Animals, MESH: Nephrotic Syndrome, Carrier Proteins, Spatial relationship, MESH : Apoptosis
Abstract

International audience; The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-κB may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-κB has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-κB family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of RelA prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a close spatial relationship. These results suggest that alterations in NF-κB activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS.

Published
2012
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6. Dynamic processes that reflect anti-apoptotic strategies set up by HspB1 (Hsp27)

Author

Sophie Virot, Florence Manero, Stéphanie Simon, André-Patrick Arrigo, Catherine Paul, Benjamin Gibert, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH : Staurosporine, MESH : Cytochromes c, MESH : HSP27 Heat-Shock Proteins, HSP27 Heat-Shock Proteins, MESH : Actins, Fluorescent Antibody Technique, Apoptosis, MESH : Blotting, Western, MESH : Antineoplastic Agents, Phytogenic, chemistry.chemical_compound, MESH : Phosphorylation, 0302 clinical medicine, MESH: Caspase 3, Staurosporine, Cytochalasin, MESH : Caspase 3, Enzyme Inhibitors, Phosphorylation, MESH: Fluorescent Antibody Technique, Heat-Shock Proteins, Cytochalasin D, Etoposide, MESH: Etoposide, 0303 health sciences, Caspase 3, Cytochromes c, MESH: Cytochromes c, MESH : Heat-Shock Response, Cell biology, Mitochondria, MESH: Antigens, CD95, MESH: Cytochalasin D, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, MESH : Mitochondria, Signal transduction, medicine.drug, Signal Transduction, MESH: Enzyme Activation, animal structures, MESH: Mitochondria, Blotting, Western, MESH: Antineoplastic Agents, Phytogenic, Biology, MESH : Etoposide, MESH: Actins, 03 medical and health sciences, Death-associated protein 6, Hsp27, MESH: Nucleic Acid Synthesis Inhibitors, medicine, Humans, MESH: Blotting, Western, MESH : HeLa Cells, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, fas Receptor, MESH: HSP27 Heat-Shock Proteins, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Nucleic Acid Synthesis Inhibitors, MESH : Signal Transduction, MESH : Enzyme Inhibitors, MESH: Humans, MESH: Phosphorylation, MESH: Apoptosis, MESH : Humans, Cell Biology, Antineoplastic Agents, Phytogenic, Actins, Enzyme Activation, MESH : Fluorescent Antibody Technique, chemistry, MESH: Heat-Shock Response, MESH: HeLa Cells, biology.protein, MESH: Staurosporine, MESH : Antigens, CD95, MESH : Cytochalasin D, MESH : Nucleic Acid Synthesis Inhibitors, MESH : Enzyme Activation, MESH : Apoptosis, Heat-Shock Response, HeLa Cells, Molecular Chaperones
Abstract

International audience; Human HspB1 (also denoted Hsp27) is an oligomeric anti-apoptotic protein that has tumorigenic and metastatic roles. To approach the structural organizations of HspB1 that are active in response to apoptosis inducers acting through different pathways, we have analyzed the relative protective efficiency induced by this protein as well its localization, oligomerization and phosphorylation. HeLa cells, that constitutively express high levels of HspB1 were treated with either etoposide, Fas agonist antibody, staurosporine or cytochalasin D. Variability in HspB1 efficiency to interfere with the different apoptotic transduction pathways induced by these agents were detected. Moreover, inducer-specific dynamic changes in HspB1 localization, native size and phosphorylation were observed, that differed from those observed after heat shock. Etoposide and Fas treatments gradually shifted HspB1 towards large but differently phosphorylated oligomeric structures. In contrast, staurosporine and cytochalasin D induced the rapid but transient formation of small oligomers before large structures were formed. These events correlated with inducer-specific phosphorylations of HspB1. Of interest, the formation of small oligomers in response to staurosporine and cytochalasin D was time correlated with the rapid disruption of F-actin. The subsequent, or gradual in the case of etoposide and Fas, formation of large oligomeric structures was a later event concomitant with the early phase of caspase activation. These observations support the hypothesis that HspB1 has the ability, through specific changes in its structural organization, to adapt and interfere at several levels with challenges triggered by different signal transduction pathways upstream of the execution phase of apoptosis.

Published
2010
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7. Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner

Author

Nathalie Andrieu-Abadie, Virginie Garcia, Hélène Autefage, Nicole Therville, Thierry Levade, Marie-Françoise Altié, Catherine Caillaud, Virginie Albinet, Hortense Berges, Marie-Laure Nicolau, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -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], 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 Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise

Subjects
Small interfering RNA, MESH : Cytochromes c, MESH: Neurons, MESH: Cricetinae, Apoptosis, MESH: Caspase 9, Biochemistry, Aminopeptidases, MESH: Recombinant Proteins, MESH: Cricetulus, Cricetinae, MESH: Caspase 3, MESH : CHO Cells, MESH : Catalysis, MESH: Animals, MESH : Caspase 3, MESH: Endopeptidases, Caspase, Neurons, MESH : Tumor Necrosis Factor-alpha, biology, Tripeptidyl-Peptidase 1, MESH : Caspase 9, Caspase 3, Mechanisms of Signal Transduction, MESH : Cricetinae, Cytochromes c, Transfection, MESH: Cytochromes c, Caspase 9, Recombinant Proteins, MESH : Endopeptidases, Cell biology, Tumor necrosis factor alpha, BH3 Interacting Domain Death Agonist Protein, Programmed cell death, Proteases, MESH : Recombinant Proteins, MESH : Cricetulus, MESH: BH3 Interacting Domain Death Agonist Protein, CHO Cells, Catalysis, MESH : Neurons, Cricetulus, MESH: CHO Cells, Endopeptidases, MESH : Fibroblasts, Animals, Humans, MESH : BH3 Interacting Domain Death Agonist Protein, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Molecular Biology, Serine protease, MESH: Humans, Tumor Necrosis Factor-alpha, MESH: Apoptosis, MESH : Humans, Cell Biology, Fibroblasts, MESH : Lysosomes, MESH: Catalysis, Molecular biology, MESH: Fibroblasts, MESH: Tumor Necrosis Factor-alpha, biology.protein, MESH : Animals, Serine Proteases, Lysosomes, MESH : Apoptosis, MESH: Lysosomes
Abstract

International audience; Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. Although caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes has only recently been unmasked. This study investigated the role of the lysosomal serine protease CLN2 in apoptosis. We report that cells isolated from patients affected with late infantile neuronal ceroid lipofuscinosis (LINCL) having a deficient activity of CLN2 are resistant to the toxic effect of death ligands such as tumor necrosis factor (TNF), CD95 ligand, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not to receptor-independent stress agents. CLN2-deficient cells exhibited a defect in TNF-induced Bid cleavage, release of cytochrome c, and caspase-9 and -3 activation. Moreover, extracts from CLN2-overexpressing cells or a CLN2 recombinant protein were able to catalyze the in vitro cleavage of Bid. Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity. Conversely, transfection of CLN2-corrected cells with small interfering RNA targeting Bid abrogated TNF-induced cell death. Altogether, our study demonstrates that genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells, indicating that CLN2 plays a yet unsuspected role in TNF-induced cell death.

Published
2009
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8. Effects of subchronic digestive exposure to organic or inorganic cadmium on biomarkers in rat tissues

Author

Sylvie Devaux, Alain Berthelot, R.P. Cosson, Renaud Scheifler, Lysiane Richert, Hélène Martin, F. Hispard, Pierre-Marie Badot, A. de Vaufleury, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Unité sous contrat biologie environnementale, Institut National de la Recherche Agronomique (INRA)-Université de Franche-Comté (UFC), Optimisation Métabolique et Cellulaire, Université de Franche-Comté (UFC), Mer, molécules et santé EA 2160 (MMS), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Biologie Marine, Université de Nantes (UN)-ISOMer, ADEME (Agence De l'Environnement et de la Maîtrise de l'Energie, contract n° 0175037 and 0572 C0058), ANR-05-ECCO-0004,STARTT,Biodisponibilité, transferts et effets des éléments trace métalliques dans des réseaux trophiques terrestres : changements d'échelle spatiale et de niveau d'organisation biologique(2005), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Institut National de la Recherche Agronomique ( INRA ) -Université de Franche-Comté ( UFC ), Université de Franche-Comté ( UFC ), Mer, molécules et santé ( MMS ), Université de Nantes ( UN ), Université de Nantes ( UN ) -ISOMer, programme STARTT, ANR-05-ECC0-004,programme STARTT, ANR-05-ECC0-004, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Le Mans Université (UM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques

Subjects
MESH : Alanine Transaminase, Snails, Wistar, Small, 01 natural sciences, MESH: Lipid Peroxidation, Lipid peroxidation, MESH: gamma-Glutamyltransferase, Malondialdehyde, Metallothionein, MESH: Animals, MESH: Snails, MESH : Cadmium, MESH : Environmental Pollutants, chemistry.chemical_classification, 0303 health sciences, Cadmium, MESH : Intestine, Small, Glutathione peroxidase, General Medicine, gamma-Glutamyltransferase, Pollution, MESH : Food Chain, Intestine, MESH: Environmental Pollutants, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, medicine.medical_specialty, Food Chain, MESH : Glutathione Peroxidase, MESH : Aspartate Aminotransferases, 03 medical and health sciences, MESH: Aspartate Aminotransferases, MESH: Catalase, Aspartate Aminotransferases, Rats, Wistar, Myocardium, MESH: Metallothionein, Public Health, Environmental and Occupational Health, Kidney metabolism, MESH : Metallothionein, Endocrinology, chemistry, MESH : Snails, MESH: Glutathione Peroxidase, Lipid Peroxidation, MESH: Female, Biomarkers, MESH: Liver, MESH: Intestine, Small, Health, Toxicology and Mutagenesis, [ SDV.TOX.ECO ] Life Sciences [q-bio]/Toxicology/Ecotoxicology, 010501 environmental sciences, Kidney, chemistry.chemical_compound, Intestine, Small, MESH: Caspase 3, MESH : Myocardium, MESH : Caspase 3, MESH : Female, Gamma-glutamyltransferase, biology, MESH : Lipid Peroxidation, MESH : Rats, Caspase 3, Alanine Transaminase, Catalase, MESH : Kidney, Biochemistry, Liver, Biological Markers, Environmental Pollutants, Female, MESH: Myocardium, MESH: Rats, MESH: Malondialdehyde, MESH: Cadmium, chemistry.chemical_element, MESH : Rats, Wistar, MESH : Catalase, Internal medicine, medicine, Animals, MESH: Food Chain, 030304 developmental biology, 0105 earth and related environmental sciences, MESH : Malondialdehyde, Glutathione Peroxidase, MESH: Biological Markers, MESH : Liver, MESH: Kidney, MESH: Rats, Wistar, Rats, MESH : Biological Markers, MESH: Alanine Transaminase, biology.protein, MESH : Animals, MESH : gamma-Glutamyltransferase
Abstract

International audience; In an experimental food chain, Wistar rats were fed cadmium (Cd) in an inorganic (CdCl(2)) or organic (mainly associated with metallothionein from Helix aspersa snail viscera) form. After 1 month of exposure to 100 microg inorganic Cd g(-1) in food, an induction of metallothionein was observed in all target tissues. In liver, glutathione peroxidase (GSH-Px) activity decreased and alanine aminotransferase (ALAT) activity increased, suggesting that Cd causes hepatotoxicity. However, lipid peroxidation as well as catalase and caspase 3 (a marker of apoptosis) activities were not modified. At a rather low exposure (2.5 microg Cd g(-1)), metallothionein level in the kidney was found to be the most sensitive biomarker of exposure for both Cd forms. In the small intestine of rats ingesting inorganic Cd, metallothionein expression was significantly higher than that observed for rats fed organic Cd. Present results allowed proposing a simple design to assess the effect of a chemical in a trophic transfer approach.

Published
2008
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9. Characterization of a serine protease-mediated cell death program activated in human leukemia cells

Author

A R, O'Connell, C, Holohan, A, Torriglia, B W, Lee, B F, Lee, C, Stenson-Cox, Torriglia, Alicia, National Centre for Biomedical Engineering Science and Department of Biochemistry, National University of Ireland [Galway] ( NUI Galway ), Physiopathologie des Maladies Oculaires : Innovations Therapeutiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunochemistry Technologies LLC., Immunochemistry Technologies LLC, National University of Ireland [Galway] (NUI Galway), and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH : Staurosporine, Cell, MESH: Chymases, MESH : Chymases, Apoptosis, MESH : Blotting, Western, Serine, MESH: Caspase 3, Staurosporine, MESH : Caspase 3, MESH: Serine Endopeptidases, Caspase, biology, Caspase 3, Serine Endopeptidases, MESH : HL-60 Cells, Caspase Inhibitors, Cell biology, medicine.anatomical_structure, Biochemistry, Caspases, medicine.drug, Subcellular Fractions, Proteases, Programmed cell death, Serine Proteinase Inhibitors, MESH: Serine Proteinase Inhibitors, Blotting, Western, HL-60 Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH : Serine Proteinase Inhibitors, MESH : Subcellular Fractions, Chymases, MESH: HL-60 Cells, MESH : Serine Endopeptidases, medicine, MESH: Blotting, Western, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Serine protease, MESH: Caspases, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Apoptosis, MESH : Humans, Cell Biology, MESH: Subcellular Fractions, biology.protein, MESH: Staurosporine, MESH : Caspases, MESH : Apoptosis
Abstract

Tightly controlled proteolysis is a defining feature of apoptosis and caspases are critical in this regard. Significant roles for non-caspase proteases in cell death have been highlighted. Staurosporine causes a rapid induction of apoptosis in virtually all mammalian cell types. Numerous studies demonstrate that staurosporine can activate cell death under caspase-inhibiting circumstances. The aim of this study was to investigate the proteolytic mechanisms responsible for cell death under these conditions. To that end, we show that inhibitors of serine proteases can delay cell death in one such system. Furthermore, through profiling of proteolytic activation, we demonstrate, for the first time, that staurosporine activates a chymotrypsin-like serine protease-dependent cell death in HL-60 cells independently, but in parallel with the caspase controlled systems. Features of the serine protease-mediated system include cell shrinkage and apoptotic morphology, regulation of caspase-3, altered nuclear morphology, generation of an endonuclease and DNA degradation. We also demonstrate a staurosporine-induced activation of a putative 16 kDa chymotrypsin-like protein during apoptosis.

Published
2006
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10. Controlling TRAIL-mediated caspase-3 activation

Author

Delphine Merino, Olivier Micheau, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Micheau, Olivier

Subjects
Cancer Research, T-Lymphocytes, MESH: Membrane Glycoproteins, Apoptosis, MESH : Membrane Glycoproteins, Jurkat cells, MESH : Proto-Oncogene Proteins c-bcl-2, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, 0302 clinical medicine, MESH: Caspase 3, MESH : Caspase 3, Caspase, bcl-2-Associated X Protein, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, Leukemia, Membrane Glycoproteins, biology, Caspase 3, MESH: Mitochondrial Proteins, MESH: Adenoviridae, Hematology, Mitochondria, 3. Good health, Cell biology, bcl-2 Homologous Antagonist-Killer Protein, Proto-Oncogene Proteins c-bcl-2, Oncology, Caspases, 030220 oncology & carcinogenesis, MESH : Proto-Oncogene Proteins, MESH : Mitochondria, MESH: Membrane Proteins, biological phenomena, cell phenomena, and immunity, MESH : Apoptosis Regulatory Proteins, MESH: TNF-Related Apoptosis-Inducing Ligand, Bcl-2 Homologous Antagonist-Killer Protein, Programmed cell death, MESH: Enzyme Activation, MESH: Mitochondria, Adenoviridae, Mitochondrial Proteins, 03 medical and health sciences, Bcl-2-associated X protein, Proto-Oncogene Proteins, MESH: Leukemia, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: bcl-2-Associated X Protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Adenoviridae, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Mitochondrial Proteins, 030304 developmental biology, Death domain, MESH : T-Lymphocytes, MESH: Caspases, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : bcl-2-Associated X Protein, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH : Humans, MESH : Leukemia, Membrane Proteins, MESH : bcl-2 Homologous Antagonist-Killer Protein, Enzyme Activation, MESH: Proto-Oncogene Proteins, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH : Membrane Proteins, MESH: Tumor Necrosis Factor-alpha, biology.protein, MESH : Caspases, Apoptosis Regulatory Proteins, MESH : Enzyme Activation, MESH: bcl-2 Homologous Antagonist-Killer Protein, MESH : Apoptosis
Abstract

This commentary is addressed at the paper by Dr Jie and his co-workers in the current issue of Leukemia (‘Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells’). In this paper, the authors show the preferential use of Bax over Bak for the induction of mitochondrial apoptotic events in leukemic cell exposed to TRAIL 1. These findings are consistent with previous studies involving Bax in TRAIL-mediated apoptosis in the colon carcinoma cell line HCT116 2–4. The redundant function of Bak and Bax was initially demonstrated in lymphocytes subjected to various apoptotic stimuli 5–8. Hence, simultaneous Bax and Bak gene inactivation results in a profound effect on the control of lymphocyte survival upon growth factor or glucose deprivation 9. Whereas, Bak inactivation, alone, appears to have no effect, Bax inactivation, however, slightly affected lymphocyte survival 9. These data could therefore suggest that Bax and Bak may not be so redundant after all. Accordingly, the use of Jurkat clones deficient for both Bak and Bax by Jie and collaborators, revealed that Bax and Bak could exhibit differential functions, at least in the studied cell type system, as only Bax re-expression could restore caspase-3 processing and sensitization to TRAIL-induced cell death 1. Loss of function mutations of Bax are often found both in colon carcinomas 10 and in leukemias 11,12. Therefore, since both death domain containing receptors and chemotherapeutic agents may require Bax for the triggering of the apoptotic process 2,13, this information may be important for future cancer therapeutic approaches using TRAIL or TRAIL receptor agonists either alone or in combination with chemotherapeutic agents.

Published
2004
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