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Start Over Author "Mathieu, Boissan" Topic 0302 clinical medicine
21 results on '"Mathieu, Boissan"'

1. Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

Author

Laetitia Fuhrmann, Ivan Bièche, Marie Irondelle, Fabien Reyal, Anne Houdusse, Olena Pylypenko, Stephen J. Weiss, Olivier De Wever, Mathieu Boissan, Anne Vincent-Salomon, Catalina Lodillinsky, Claire Calmel, Ana María Eiján, Philippe Chavrier, Hélène Bonsang-Kitzis, Marie-Lise Lacombe, Sophie Vacher, Xiao Yan Li, Universidad de Buenos Aires [Buenos Aires] (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Institut Curie [Paris], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Michigan [Ann Arbor], University of Michigan System, Centre de Recherche Saint-Antoine (CR Saint-Antoine), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ghent University Hospital, Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Neurobiologie des Canaux Ioniques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de chirurgie, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Pylypenko, Olena, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de la Méditerranée - Aix-Marseille 2, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
0301 basic medicine, Cancer Research, TUMOR-CELLS, [SDV]Life Sciences [q-bio], Endocytic cycle, PROGRESSION, Matrix metalloproteinase, Extracellular matrix, Dynamin II, Mice, Breast cancer, 0302 clinical medicine, Membrane fission, Cell Movement, Medicine and Health Sciences, Neoplasm Metastasis, skin and connective tissue diseases, Middle Aged, NM23 Nucleoside Diphosphate Kinases, Endocytosis, Extracellular Matrix, [SDV] Life Sciences [q-bio], CARCINOMA IN-SITU, 030220 oncology & carcinogenesis, Female, TRANSITION, DYNAMIN, MIGRATION, Mice, Nude, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, Matrix Metalloproteinase 14, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, Humans, TRAFFICKING, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Metastasis suppressor, Molecular Biology, Neoplasm Staging, Carcinoma in situ, MICROINVASION, Ductal carcinoma, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research
Abstract

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.

Published
2021
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2. The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Author

Zsolt Farkas, Anil Mehta, Anna Sebestyén, Krisztina Takács-Vellai, Barbara Mátyási, Mathieu Boissan, László Kopper, Embertani Tanszék, MTA-SE Molekuláris Pathológiai Kutatócsoport (2006 végéig működött), Biológia Doktori Iskola, Genetikai Tanszék, MTA-SE Molekuláris Onkológia Kutatócsoport, and I. Sz. Patológiai és Kísérleti Rákkutató Intézet

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, Apoptosis, Review, Biology, Endocytosis, NDPK, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Phagocytosis, Cell Movement, Animals, Humans, Cell migration, Neoplasm Invasiveness, Neoplasm Metastasis, Dynamin, Cell Proliferation, Metastasis inhibitor, Kinase, Chemotaxis, General Medicine, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Cell biology, Metastasis Suppressor Gene, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Nucleoside-Diphosphate Kinase, Cftr, Phosphohistidine, NM23
Abstract

Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for non-metastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.

Published
2020

3. Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells

Author

David Bernard, Sylvie Coscoy, Teresita Padilla-Benavides, Anda Huna, Julie Gavard, B. Nawrocki-Raby, Mathieu Boissan, 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), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wesleyan University, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département d'Oncologie [Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe labellisée Ligue contre le Cancer, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Bernardo, Elizabeth

Subjects
Epithelial-Mesenchymal Transition, MAP Kinase Signaling System, Cell, Mice, Nude, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, epithelial–mesenchymal transition, Catalysis, Article, Metastasis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Cell Adhesion, Animals, Humans, cancer, metastasis, Metastasis suppressor, Epithelial–mesenchymal transition, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Protein kinase B, Spectroscopy, 030304 developmental biology, Gene Editing, 0303 health sciences, Chemistry, Organic Chemistry, Mesenchymal stem cell, Cancer, General Medicine, NM23 Nucleoside Diphosphate Kinases, medicine.disease, Cadherins, Computer Science Applications, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female, epithelium
Abstract

International audience; Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, by using gene silencing, inactivation and overexpression strategies in a variety of cellular models of cancer, we show that NME1 is a powerful inhibitor of EMT. Genetic manipulation of NME2, by contrast, had no effect on the EMT phenotype of cancer cells, indicating a specific function of NME1 in EMT regulation. Loss of NME1 in epithelial cancer cells resulted in a hybrid phenotype intermediate between epithelial and mesenchymal cells, which is known to be associated with cells with a highly metastatic character. Conversely, overexpression of NME1 in mesenchymal cancer cells resulted in a more epithelial phenotype. We found that NME1 expression was negatively associated with EMT markers in many human cancers and was reduced in human breast tumor cell lines with the aggressive ‘triple-negative’ phenotype when compared to human breast tumor cell lines positive for estrogen receptor. We show that NME1, but not NME2, is an inhibitor of essential concerted intracellular signaling pathways involved in inducing EMT, including the AKT and MAPK (ERK, p38, and JNK) pathways. Additionally, NME1 depletion considerably altered the distribution of E-cadherin, a gatekeeper of the epithelial phenotype, shifting it from the plasma membrane to the cytosol and resulting in less E-cadherin on the cell surface than in control cells. Functional aggregation and dispersion assays demonstrated that inactivation of NME1 decreases E-cadherin-mediated cell–cell adhesion. We conclude that NME1, but not NME2, acts specifically to inhibit EMT and prevent the earliest stages of metastasis.

Published
2021
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4. Massive lactic acidosis and ketoacidosis with glucagon deficiency in a chronic alcoholic patient

Author

Patrick Gilon, Philippe Boudou, Fabrizio Andreelli, Michel Djibré, Pascal Ferré, Soraya Fellahi, Fidaa Ibrahim, Mathieu Boissan, and UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition

Subjects
2. Zero hunger, 0303 health sciences, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Chronic alcoholic, 030209 endocrinology & metabolism, General Medicine, medicine.disease, Glucagon Deficiency, Gastroenterology, 3. Good health, Ketoacidosis, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Lactic acidosis, Internal Medicine, medicine, business, 030304 developmental biology
Abstract

A non-diabetic chronic alcoholic and undernourished male patient [body mass index (BMI): 16.6 kg/m2] was admitted to our hospital emergency department. He had fasted for the previous 3 days. His blood lactate and ketone body concentrations were massively elevated (18 mmol/L and 14 mmol/L, respectively). Ethanolaemia was negative. Massive metabolic acidosis was noted with a pH of 7.04. Renal function remained normal, but there was mild hepatocellular deficiency and no acute pancreatitis. The patient was hypoglycaemic at admission with a blood glucose level of 3.0 mmol/L, and low concentrations of insulin, C-peptide and insulin-like growth factor (IGF)-1, as well as very low glucagon concentrations (5.2 ng/L; normal range: 8–74 ng/L) despite the prevailing glycaemia. In contrast, cortisol, sex hormone-binding globulin (SHBG) and growth hormone (GH) concentrations were elevated. [...]

Published
2021

5. The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor

Author

David Bernard, Malgorzata Tokarska-Schlattner, Anda Huna, Patrice Thérond, Isabelle Hininger-Favier, Sophie Vacher, Patricia S. Steeg, Céline Desbourdes, Guilhem Clary, Philippe Chafey, Morgane Le Gall, Imran Khan, Jérôme Guitton, Olivier De Wever, Christelle Machon, Alyssa Carlson, Ivan Bièche, Teresita Padilla-Benavides, Cécile Cottet-Rousselle, Uwe Schlattner, Stéphane Attia, Béatrice Nawrocki-Raby, Cédric Broussard, Frédéric Lamarche, Mathieu Boissan, Joël Raingeaud, Marie-Lise Lacombe, Claire Calmel, Eric Fontaine, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Universiteit Gent = Ghent University [Belgium] (UGENT), Wesleyan University, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), 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), Centre Léon Bérard [Lyon], Institut Curie [Paris], Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Biostatistique, traitement et modélisation des données biologiques (BioSDTM - URP_7537), Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), raingeaud, joel, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universiteit Gent = Ghent University (UGENT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
DYNAMICS, Physiology, MATRIX METALLOPROTEINASES, [SDV]Life Sciences [q-bio], PROMOTES METASTASIS, PROTEIN, Plant Science, Mitochondrion, Metastasis, Mice, 0302 clinical medicine, Invasion, Structural Biology, Neoplasms, Medicine and Health Sciences, Biology (General), Nucleoside Diphosphate Kinase D, 0303 health sciences, Ecology, Metabolic reprogramming, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Mitochondria, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SYNUCLEIN-GAMMA, Intermembrane space, General Agricultural and Biological Sciences, Research Article, Biotechnology, QH301-705.5, Evolution, NM23-H4, Genetics and Molecular Biology, Nucleoside diphosphate kinase, Biology, Prognosis biomarker, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Behavior and Systematics, Animals, BREAST-CANCER, Metastasis suppressor, CELL, Kinase activity, Retrograde signaling, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, NME4, Intracellular Membranes, Cell Biology, GENE, Metastasis Suppressor Gene, Nucleoside-Diphosphate Kinase, Cancer cell, General Biochemistry, Mitochondrial dynamics, MEMBRANE, Developmental Biology
Abstract

Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

Published
2021
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6. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/Dynamin

Author

Floriane Herit, Tamás I. Orbán, Metka Petric, Florence Niedergang, Zsuzsa Bajtay, Anil Mehta, Xianghua Liu, Mathieu Boissan, Tibor Kovács, Zsófia Budai, Jun Qin, Zsolt Farkas, Muhammed Afaq Shakir, Zheng Zhou, Sára Sándor, Sung Yun Jung, Krisztina Takács-Vellai, Éva Rajnavölgyi, Zsuzsa Szondy, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Debrecen Egyetem [Debrecen], Biochemistry and Molecular Biology, Division of Medical Sciences, University of Dundee, University of Maryland [College Park], University of Maryland System, CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Dynamins, Phagocytosis, metastasis inhibitor, apoptotic clearance, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Phagosomes, Phagosome maturation, Genetics, Animals, Humans, Receptor, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Molecular Biology, Opsonin, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Dynamin, Chemistry, Research, Macrophages, phagosome maturation, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Actins, Cell biology, Mice, Inbred C57BL, Signaling network, 030104 developmental biology, Leukocytes, Mononuclear, phagosome formation, 030217 neurology & neurosurgery, Biotechnology, actin cup, Signal Transduction
Abstract

Phagocytosis of various targets, such as apoptotic cells or opsonized pathogens, by macrophages is coordinated by a complex signaling network initiated by distinct phagocytic receptors. Despite the different initial signaling pathways, each pathway ends up regulating the actin cytoskeletal network, phagosome formation and closure, and phagosome maturation leading to degradation of the engulfed particle. Herein, we describe a new phagocytic function for the nucleoside diphosphate kinase 1 (NDK-1), the nematode counterpart of the first identified metastasis inhibitor NM23-H1 (nonmetastatic clone number 23) nonmetastatic clone number 23 or nonmetastatic isoform 1 (NME1). We reveal by coimmunoprecipitation, Duolink proximity ligation assay, and mass spectrometry that NDK-1/NME1 works in a complex with DYN-1/Dynamin (Caenorhabditis elegans/human homolog proteins), which is essential for engulfment and phagosome maturation. Time-lapse microscopy shows that NDK-1 is expressed on phagosomal surfaces during cell corpse clearance in the same time window as DYN-1. Silencing of NM23-M1 in mouse bone marrow–derived macrophages resulted in decreased phagocytosis of apoptotic thymocytes. In human macrophages, NM23-H1 and Dynamin are corecruited at sites of phagosome formation in F-actin–rich cups. In addition, NM23-H1 was required for efficient phagocytosis. Together, our data demonstrate that NDK-1/NME1 is an evolutionarily conserved element of successful phagocytosis.—Farkas, Z., Petric, M., Liu, X., Herit, F., Rajnavölgyi, É., Szondy, Z., Budai, Z., Orbán, T. I., Sándor, S., Mehta, A., Bajtay, Z., Kovács, T., Jung, S. Y., Afaq Shakir, M., Qin, J., Zhou, Z., Niedergang, F., Boissan, M., Takács-Vellai, K. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/dynamin.

Published
2019
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7. Meningococcal purpura fulminans and severe myocarditis with clinical meningitis but no meningeal inflammation: a case report

Author

Patricia Senet, Muriel Fartoukh, Charlotte Verdet, Marc Garnier, Nicolas Derre, Gilles Pialoux, Olivier Gaudin, Mehdi Hage-Sleiman, Mathieu Boissan, Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service des soins intensifs [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Maladies infectieuses et tropicales [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Anatomopathologie [CHU Tenon], Service de dermatologie et allergologie [CHU Tenon], Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Gestionnaire, Hal Sorbonne Université, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service des maladies infectieuses et tropicales [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Myocarditis, Fulminant, 030106 microbiology, Case Report, Neisseria meningitidis, Serogroup C, Meningitis, Meningococcal, Neisseria meningitidis, medicine.disease_cause, Meningococcal disease, Gastroenterology, lcsh:Infectious and parasitic diseases, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, medicine, Humans, Meningitis, lcsh:RC109-216, Iloprost, 030212 general & internal medicine, Inflammation, Disseminated intravascular coagulation, Purpura fulminans, medicine.diagnostic_test, Lumbar puncture, business.industry, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cerebrospinal fluid, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, business
Abstract

International audience; Background: During fulminant meningococcal septicaemia, meningococci are often observed in the cerebrospinal fluid (CSF) although the patients have frequently no meningeal symptoms. Meningococcal meningitis, by contrast, usually features clinical meningeal signs and biochemical markers of inflammation with elevated white blood cell count (pleiocytosis) in the CSF. Cases of typical symptomatic meningitis without these biochemical features are uncommon in adults.Case presentation: A 21-year-old male presented with meningococcal purpura fulminans and disseminated intravascular coagulation (DIC) associated with multiple organ dysfunction syndrome requiring hospitalization in the Intensive Care Unit. Despite typical meningeal clinical signs, lumbar puncture showed no pleiocytosis, normal glycorachia and normal proteinorachia, whereas the lactate concentration in the CSF was high (5.8 mmol/L). CSF culture showed a high inoculum of serogroup C meningococci. On day 2, after initial improvement, a recurrence of hypotension led to the diagnosis of acute meningococcal myocarditis, which evolved favourably within a week. During the hospitalization, distal ischemic and necrotic lesions were observed, predominantly on the fingertips, which were treated with local and systemic vasodilators.Conclusions: We report a rare case of adult meningococcal disease characterized by an intermediate form of meningitis between purulent meningitis and meningeal inoculation from fulminant meningococcal septicaemia, without classical signs of biological inflammation. It highlights the diagnostic value of CSF lactate, which may warrant administration of a meningeal dosing regimen of beta-lactam antibiotics. This case also demonstrates the potential severity of meningococcal myocarditis; we discuss its pathophysiology, which is distinct from other sepsis-related cardiomyopathies. Finally, the observed effects of vasodilators on the meningococcal skin ischemia in this case encourages future studies to assess their efficacy in DIC-associated necrosis.

Published
2019
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8. The extracellular domain of Her2 in serum as a biomarker of breast cancer

Author

Guillaume Lefèvre, Mathieu Boissan, Alexandre Perrier, and Joseph Gligorov

Subjects
0301 basic medicine, genetic structures, Receptor, ErbB-2, Breast Neoplasms, Pathology and Forensic Medicine, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Carcinoembryonic antigen, Protein Domains, Adjuvant therapy, Biomarkers, Tumor, Medicine, Humans, Epidermal growth factor receptor, Neoplasm Metastasis, skin and connective tissue diseases, Molecular Biology, biology, business.industry, Cancer, Cell Biology, medicine.disease, Prognosis, Metastatic breast cancer, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Biomarker (medicine), Female, Neoplasm Recurrence, Local, business
Abstract

Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

Published
2017

9. An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies

Author

Pierre-Yves Boëlle, Didier Brault, Yves Chrétien, Joseph Gligorov, Mathieu Boissan, Eva Comperat, Jean-Pierre Lotz, Alexandre Perrier, Guillaume Lefèvre, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Médicale [Paris], Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, CA15-3, Receptor, ErbB-2, Physiology, Progressive Diseases, Cancer Treatment, Pathology and Laboratory Medicine, Biochemistry, Metastasis, chemistry.chemical_compound, 0302 clinical medicine, Trastuzumab, Immune Physiology, Breast Tumors, Basic Cancer Research, Medicine and Health Sciences, Neoplasm Metastasis, skin and connective tissue diseases, Immune System Proteins, Multidisciplinary, Middle Aged, Metastatic breast cancer, 3. Good health, Gene Expression Regulation, Neoplastic, Paclitaxel, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, Medicine, Biomarker (medicine), Female, Research Article, medicine.drug, Adult, medicine.medical_specialty, Science, Immunology, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Research and Analysis Methods, Disease-Free Survival, Antibodies, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Breast Cancer, Biomarkers, Tumor, medicine, Humans, Immunohistochemistry Techniques, Aged, business.industry, Mucin-1, Biology and Life Sciences, Cancers and Neoplasms, Proteins, medicine.disease, Carcinoembryonic Antigen, Monoclonal Antibodies, Histochemistry and Cytochemistry Techniques, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030104 developmental biology, chemistry, Immunologic Techniques, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Biomarkers, Progressive disease
Abstract

International audience; BACKGROUND:The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer.METHODS:We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90.RESULTS:Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.

Published
2020
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10. The advantage of channeling nucleotides for very processive functions

Author

Philippe Chavrier, Diana Zala, Mathieu Boissan, Thomas Desvignes, Julien Bobe, Aurélien Roux, Uwe Schlattner, Laboratoire Plasticité du Cerveau (PdC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Paris Sciences et Lettres (PSL), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Curie, Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fondation pour la Recherche Médicale (FRM DPM20121125557), Groupement des Entreprises Françaises contre le Cancer (GEFLUC R16170DD/RAK16044DDA), Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris ( ESPCI ParisTech ), Laboratoire de bioénergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Station commune de Recherches en Ichtyophysiologie, Biodiversité et Environnement ( SCRIBE ), Institut National de la Recherche Agronomique ( INRA ) -IFR140, Laboratoire de Physiologie et Génomique des Poissons ( LPGP ), Institut National de la Recherche Agronomique ( INRA ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'acoustique de l'université du Mans ( LAUM ), Le Mans Université ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), UMRS 938 : Saint-Antoine Research Center, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of Oregon [Eugene], Université de Genève = University of Geneva (UNIGE), Swiss National Centre for Competence in Research Programme Chemical Biology (NCCR-Chemical Biology), Institut Curie [Paris], Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Chavrier, Philippe, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, GTP', ATPase, [SDV]Life Sciences [q-bio], Review, GTPase, bioenergetics, mécanisme moléculaire, chemistry.chemical_compound, atp, 0302 clinical medicine, Cell Signaling, canalisation, General Pharmacology, Toxicology and Pharmaceutics, glycolyse, ComputingMilieux_MISCELLANEOUS, gtp, Kinase, nucleoside diphosphate kinase, Articles, General Medicine, glycolysis, Nucleoside-diphosphate kinase, [SDV] Life Sciences [q-bio], pipe, ddc:540, Nucleoside triphosphate, Glycolysis, bioénergétique, medicine.drug, métabolisme énergétique, oxidative phosphorylation, Guanosine, Nucleoside diphosphate kinase, Bioenergetics, Biology, atpase, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, dynamin, medicine, creatine kinase, Oxidative phosphorylation, Creatine kinase, General Immunology and Microbiology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, cell, Adenosine, ATP, Dynamin, 030104 developmental biology, chemistry, biology.protein, Biophysics, enzyme glycolytique, cellule, Neuroscience, GTP, 030217 neurology & neurosurgery, nucléoside triphosphatase, Membranes & Sorting
Abstract

[version 2]; International audience; Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP-or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover,. is i.e very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases. Keywords

Published
2017
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11. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling

Author

Ioan Lascu, Graça Raposo, Céline Desbourdes, Philippe Chavrier, Nathalie Sauvonnet, Thibault Lagache, Guillaume Montagnac, Jérôme Guitton, Qinfang Shen, Aurélien Roux, Marie-Lise Lacombe, Maryse Romao, Uwe Schlattner, Lorena Griparic, AlexanderM van der Bliek, Mathieu Boissan, Simona Polo, Institut Curie [Paris], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dynamique de la membrane et du cytosquelette, Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Hospices Civils de Lyon (HCL), Université de Lyon, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Cellulaires (BIC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano [Milano] (UNIMI), University of Geneva [Switzerland], This work was supported by Institut Curie, CNRS, Fondation ARC pour la Recherche sur le Cancer, Groupement des Entreprises Françaises contre le Cancer, Fondation pour la Recherche Médicale, the Human Frontier Science Program, the Swiss National Fund for Research Grant, and the European Research Council., Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI), and Université de Genève = University of Geneva (UNIGE)

Subjects
endocrine system, MESH: GTP Phosphohydrolases, GTP', MESH: Mitochondria, [SDV]Life Sciences [q-bio], MESH: Guanosine Diphosphate, Biology, Guanosine triphosphate, MESH: Membrane Fusion, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Adenosine Triphosphate, MESH: Animals, Nucleoside Diphosphate Kinase D, 030304 developmental biology, Dynamin, 0303 health sciences, Multidisciplinary, MESH: Guanosine Triphosphate, MESH: Humans, Kinase, Cell biology, MESH: Cell Line, MESH: Dynamins, MESH: Intracellular Membranes, chemistry, Guanosine diphosphate, 030220 oncology & carcinogenesis, ddc:540, MESH: Endocytosis, MESH: Coated Pits, Cell-Membrane, GTP Phosphohydrolases, MESH: NM23 Nucleoside Diphosphate Kinases, MESH: Nucleoside Diphosphate Kinase D, Adenosine triphosphate, MESH: Cell Membrane
Abstract

Supplying power: Right time, right place Cell membranes are very flexible and easily molded to shape; however, to physically pinch off a membrane vesicle from a membrane tube still requires power. A type of molecular machine known as dynamin is involved in this sort of membrane remodeling. Dynamins use guanosine triphosphate (GTP) rather than the more commonly used cellular energy source adenosine triphosphate to work. Boissan et al. now show that two separate dynamins found in the cytoplasm or the mitochondria both use the same sort of enzyme—nucleoside diphosphate kinases—to provide GTP at just the right time and the right place to power membrane fission. Science , this issue p. 1510

Published
2014
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12. Mitochondrial NM23-H4/NDPK-D: a bifunctional nanoswitch for bioenergetics and lipid signaling

Author

Malgorzata Tokarska-Schlattner, Valerian E. Kagan, Richard M. Epand, Uwe Schlattner, Mathieu Boissan, Judith Klein-Seetharaman, Marie-Lise Lacombe, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), McMaster University [Hamilton, Ontario], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), University of Warwick [Coventry], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), FRM (DPM20121125557), GEFLUC, ARC, and NIH (U19AIO68021, PO1 HL114453)

Subjects
Cardiolipins, [SDV]Life Sciences [q-bio], Adenylate kinase, Nucleoside diphosphate kinase, Apoptosis, Lipid trafficking, Mitochondrion, Biology, Mitochondrial apoptosis-induced channel, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cardiolipin, Humans, Moonlighting proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Inner mitochondrial membrane, 030304 developmental biology, Pharmacology, 0303 health sciences, Membranes, Nucleoside Diphosphate Kinase D, Mitophagy, General Medicine, Mitochondrial carrier, Lipid Metabolism, Cell biology, Mitochondria, chemistry, Translocase of the inner membrane, Lipid transfer proteins, ATP–ADP translocase, Energy Metabolism, 030217 neurology & neurosurgery, NM23
Abstract

International audience; A novel paradigm for the function of the mitochondrial nucleoside diphosphate kinase NM23-H4/NDPK-D is proposed: acting as a bifunctional nanoswitch in bioenergetics and cardiolipin (CL) trafficking and signaling. Similar to some other mitochondrial proteins like cytochrome c or AIF, NM23-H4 seems to have dual functions in bioenergetics and apoptotic signaling. In its bioenergetic phosphotransfer mode, the kinase reversibly phosphorylates NDPs into NTPs, driven by mitochondrially generated ATP. Among others, this reaction can locally supply GTP to mitochondrial GTPases as shown for the dynamin-like GTPase OPA1, found in a complex together with NM23-H4. Further, NM23-H4 is functionally coupled to adenylate translocase (ANT) of the mitochondrial inner membrane (MIM), so generated ADP can stimulate respiration to rapidly regenerate ATP. The lipid transfer mode of NM23-H4 can support, dependent on the presence of CL, the transfer of anionic lipids between membranes in vitro and the sorting of CL from its mitochondrial sites of synthesis (MIM) to the mitochondrial outer membrane (MOM) in vivo. Such (partial) collapse of MIM/MOM CL asymmetry results in CL externalization on the mitochondrial surface, where CL can serve as pro-apoptotic or pro-mitophagic “eat me”-signal. The functional state of NM23-H4 depends on its degree of CL-membrane interaction. In vitro assays have shown that only NM23-H4 that fully cross-links two membranes is lipid transfer competent, but at the same time phosphotransfer (kinase) inactive. Thus, the two functions of NM23-H4 seem to be mutually exclusive. This novel mitochondrial regulatory circuit has potential for the development of interventions in various human pathologies.

Published
2014
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13. Mitochondrial Nm23-H4/NDPK-D is Multifunctional: Intermembrane Cardiolipin Transfer Linked to Apoptosis

Author

Richard M. Epand, Malgorzata Tokarska-Schlattner, Sacnicte Ramirez, Yulia Y. Tyurina, Marie-Lise Lacombe, Mathieu Boissan, Uwe Schlattner, Andrew A. Amoscato, Dariush Mohammadsanyi, Judith Klein-Seetharaman, Raquel F. Epand, Zhentai Huang, Jianfei Jiang, Valerian E. Kagan, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], University of Warwick [Coventry], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0303 health sciences, biology, Mitochondrial intermembrane space, Cytochrome c, [SDV]Life Sciences [q-bio], Biophysics, Intermembrane lipid transfer, Nucleoside-diphosphate kinase, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, Cytosol, 0302 clinical medicine, chemistry, Biochemistry, Cardiolipin, biology.protein, lipids (amino acids, peptides, and proteins), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Intermembrane space, Inner mitochondrial membrane, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; Nm23-H4/NDPK-D forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. The well established function of the enzyme is phosphotransfer activity as a nucleoside diphosphate kinase (NDPK), using mitochondrial ATP to regenerate nucleoside triphosphates. Nm23-H4 is further known to strongly bind in vitro to anionic phospholipids, mainly cardiolipin, and in vivo to inner mitochondrial membranes. We show here that such protein/lipid complexes inhibit NDPK activity but are necessary for Nm23-H4 to function in selective intermembrane lipid transfer. Nm23-H4-deficient HeLa cells expressing either wild-type Nm23-H4 or a membrane-binding deficient mutant were analyzed by membrane fractionation and LC-ESI-MS. Data revealed that wild-type Nm24-H4 increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. This correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin V binding, elevated caspase 3/7 activity and stimulated release of cytochrome c into the cytosol. Molecular modeling of Nm23-H4 binding with cardiolipin reveals potential intermembrane transfer mechanisms. We propose that Nm23-H4 acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling.

Published
2013
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14. KIF20A mRNA and Its Product MKlp2 Are Increased During Hepatocyte Proliferation and Hepatocarcinogenesis

Author

Florence Bourgain-Guglielmetti, Dominique Wendum, Mathieu Boissan, Jessica Zucman-Rossi, Gabrielle Couchy, Marie-Lise Lacombe, Joëlle Sobczak-Thépot, Chantal Desdouets, Germain Margall-Ducos, Isabelle Gasnereau, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), University Paris, CNRS, INSERM, La Ligue Comite de Paris [RS06/75-57], Ligue Nationale Contre le Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, Carcinoma, Hepatocellular, Kinesins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tumor Cells, Cultured, medicine, Animals, Humans, Mitosis, Aged, 030304 developmental biology, 0303 health sciences, Gene knockdown, Cell growth, Endoplasmic reticulum, Cell Cycle, Liver Neoplasms, Middle Aged, Cell cycle, Liver regeneration, Liver Regeneration, Cell biology, Mice, Inbred C57BL, Cell Transformation, Neoplastic, Ki-67 Antigen, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, Hepatocytes, Cancer research, Female, Mitogens, Precancerous Conditions, Cytokinesis
Abstract

International audience; Mitotic kinesin-like protein 2 (MKlp2), a microtubule-associated motor, is required during mitosis exit for the final step of cytokine;is. It also contributes to retrograde vesicular trafficking from the Golgi apparatus to the endoplasmic reticulum in interphase. The KIF20A gene encoding MKlp2 is controlled by the E2F-retinoblastoma protein-p16 pathway, and its widely expressed mRNA is found in fetal and proliferating adult tissues. The expression pattern and function of MKlp2 in the adult liver, however, have not been investigated. We report herein that MKlp2 transiently accumulates in vivo during mouse liver regeneration after partial hepatectomy and is strongly overexpressed in preneoplastic and neoplastic mouse liver. In vitro in mitogen-stimulated primary hepatocytes, MKlp2 accumulated in the nucleus during the G2 phase of the cell cycle coincident with the mitotic kinase Aurora B. Human hepatoma cell lines exhibited high levels of MKlp2; however, it was undetectable in normal human hepatocytes. RNAi-mediated MKlp2 knockdown in hepatoma cells induced polyploidization consistent with its essential function in promoting cytokinesis and inhibited cell proliferation without inducing apoptosis. KIF20A mRNA was strongly accumulated in a large series of human hepatocellular carcinomas, with the highest expression observed in tumors with genomic instability. Accumulation of MKlp2 in normal proliferating, preneoplastic, and transformed hepatocytes suggests that MKlp2 contributes to both normal and pathologic hepatocyte proliferation and is linked to tumor aggressiveness in human hepatocellular carcinomas.

Published
2012
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15. Proteomic analysis of NME1/NDPK A null mouse liver: evidence for a post-translational regulation of annexin IV and EF-1Bα

Author

Bruno Baudin, Joëlle Vinh, Mathieu Boissan, Arnaud Bruneel, Marie-Lise Lacombe, Valérie Labas, Odile Mulner-Lorillon, Chantal Housset, Dominique Wendum, Sandrine Dabernat, Eric Ballot, Nelly Bosselut, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de Gestion Scientifique i3 (CGS i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut interdisciplinaire de l’innovation (I3), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CNRS/ESPCI ParisTech USR 3149, Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [APHP], and Centre de Recherche Saint-Antoine (CR Saint-Antoine)

Subjects
Genetically modified mouse, Male, Proteomics, Blotting, Western, Biology, Endoplasmic Reticulum, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Mice, 0302 clinical medicine, Cytosol, Peptide Elongation Factor 1, Tandem Mass Spectrometry, Cell Line, Tumor, Animals, Humans, Post-translational regulation, Metastasis suppressor, Electrophoresis, Gel, Two-Dimensional, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Annexin A4, 030304 developmental biology, Pharmacology, Mice, Knockout, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Endoplasmic reticulum, Wild type, General Medicine, NM23 Nucleoside Diphosphate Kinases, Molecular biology, Eukaryotic translation elongation factor 1 alpha 1, Cell biology, Protein Transport, Liver, 030220 oncology & carcinogenesis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Proteome, Protein Processing, Post-Translational, Annexin A2
Abstract

International audience; NME/NDPK family proteins are involved in the control of intracellular nucleotide homeostasis as well as in both physiological and pathological cellular processes, such as proliferation, differentiation, development, apoptosis, and metastasis dissemination, through mechanisms still largely unknown. One family member, NME1/NDPK-A, is a metastasis suppressor, yet the primary physiological functions of this protein are still missing. The purpose of this study was to identify new NME1/NDPK-A-dependent biological functions and pathways regulated by this gene in the liver. We analyzed the proteomes of wild-type and transgenic NME1-null mouse livers by combining two-dimensional gel electrophoresis and mass spectrometry (matrix-assisted laser desorption/ionization time of flight and liquid chromatography-tandem mass spectrometry). We found that the levels of three proteins, namely, phenylalanine hydroxylase, annexin IV, and elongation factor 1 Bα (EF-1Bα), were strongly reduced in the cytosolic fraction of NME1(-/-) mouse livers when compared to the wild type. This was confirmed by immunoblotting analysis. No concomitant reduction in the corresponding messenger RNAs or of total protein level was observed, however, suggesting that NME1 controls annexin IV and EF-1Bα amounts by post-translational mechanisms. NME1 deletion induced a change in the subcellular location of annexin IV in hepatocytes resulting in enrichment of this protein at the plasma membrane. We also observed a redistribution of EF-1Bα in NME1(-/-) hepatocytes to an intracytoplasmic compartment that colocalized with a marker of the reticulum endoplasmic. Finally, we found reduced expression of annexin IV coincident with decreased NME1 expression in a panel of different carcinoma cell lines. Taken together, our data suggest for the first time that NME1 might regulate the subcellular trafficking of annexin IV and EF-1Bα. The potential role of these proteins in metastatic dissemination is discussed.

Published
2011
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16. CXCR7 is up-regulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells

Author

Bruno Turlin, Claire Piquet-Pellorce, Marie-Lise Lacombe, Michel Samson, J. Monnier, Annie L'Helgoualc'h, Nathalie Théret, Mathieu Boissan, Jessica Zucman-Rossi, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de la Recherche Agronomique (INRA), CHU Pontchaillou [Rennes], Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de recherche Phytopharmacie et Médiateurs Chimiques ( UPMC ), Institut National de la Recherche Agronomique ( INRA ), Service d'anatomopathologie, Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (UMRS893), INSERM, Ministère de l’Education Nationale de la Recherche et de la Technologie, Région Bretagne, National French Society of Gastroenterology (SNFGE), ‘Ligue contre le cancer’, ‘IFR 140’, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, Cancer Research, Chemokine, MESH : Liver Neoplasms, Hepatocellular carcinoma, MESH : Aged, MESH : Receptors, CXCR, CXCR4, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Chemokine receptor, Jurkat Cells, Mice, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH: Liver Neoplasms, MESH: Jurkat Cells, Tumor Cells, Cultured, MESH : Female, MESH: Animals, MESH: Endothelial Cells, MESH: Carcinoma, Hepatocellular, MESH : Jurkat Cells, MESH: Organ Specificity, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, Liver cell, Liver Neoplasms, MESH: Receptors, CXCR, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, Liver, Organ Specificity, 030220 oncology & carcinogenesis, Disease Progression, MESH: Disease Progression, Female, Liver cancer, MESH : Carcinoma, Hepatocellular, Carcinoma, Hepatocellular, MESH : Gene Expression Regulation, Neoplastic, MESH : Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Mice, Inbred C57BL, MESH : Organ Specificity, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, parasitic diseases, medicine, CXCL10, Animals, Humans, CXCL11, MESH : Middle Aged, MESH: Tumor Cells, Cultured, MESH: Mice, 030304 developmental biology, Aged, Receptors, CXCR, MESH: Humans, MESH : Endothelial Cells, MESH : Humans, Endothelial Cells, MESH : Disease Progression, medicine.disease, CXCR7, MESH: Male, Mice, Inbred C57BL, Hepatic stellate cell, biology.protein, Cancer research, MESH : Animals, MESH: Female
Abstract

International audience; Development of hepatocellular carcinoma (HCC) is a complex and progressive disease that involves cycles of liver cell death, inflammation, and tissue regeneration/remodelling. Chemokines and chemokine receptors play numerous and integral roles in the disease progression of HCC. Here we investigated the novel chemokine receptor CXCR7/RDC1 in HCC progression, its two known ligands CXCL12 and CXCL11, as well as the other CXCL12 receptor, CXCR4. Our results show that in a cohort of 408 human HCCs, CXCR7 and CXCL11 were significantly higher in tumours compared to normal liver controls (5- and 10-fold, respectively). Immunohistochemical (IHC) staining on human HCC sections confirmed that both CXCL11 and CXCR7 were much higher in cancer tissues. Furthermore, IHC staining revealed that CXCR7 protein was only expressed in endothelial cells whereas CXCL11 exhibited a much broader tissue expression. At the cellular level we observed that in vitro, human microvascular endothelial cells (HMEC-1) up-regulated CXCR7 under hypoxic and acidic pH conditions, which are well known characteristics of the HCC tumour micro-environment. As for its ligand, we observed that IFNγ robustly induced CXCL11 in hepatic stellate cells, hepatocytes, and HMEC-1s. In addition, in the mouse Diethylnitrosamine model of hepatocarcinogenesis we observed a very strong induction of CXCR7 and CXCL11 transcripts, confirming that CXCR7/CXCL11 up-regulation is conserved between human and mice liver cancer. Altogether, our results strongly support the hypothesis that the CXCL11/CXCR7 pathway is involved HCC progression.

Published
2011
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17. The mammalian Nm23/NDPK family: from metastasis control to cilia movement

Author

Uwe Schlattner, Evelyne Peuchant, Marie-Lise Lacombe, Sandrine Dabernat, Mathieu Boissan, Ioan Lascu, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), U876, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biochimie et Génétique Cellulaires, Université Bordeaux Segalen - Bordeaux 2, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Grellety, Marie-Lise

Subjects
Lineage (genetic), [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biology, Mitochondrion, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Animals, Humans, Nucleotide, Cilia, Neoplasm Metastasis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Gene, Phylogeny, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mammals, chemistry.chemical_classification, 0303 health sciences, Kinase, Cilium, Cell Biology, General Medicine, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Mitochondria, Isoenzymes, chemistry, Biochemistry, Nucleoside-Diphosphate Kinase, 030220 oncology & carcinogenesis, Nucleoside, Protein Binding, Signal Transduction
Abstract

Nucleoside diphosphate kinases (NDPK) are encoded by the NME genes, also called NM23. They catalyze the transfer of gamma-phosphate from nucleoside triphosphates to nucleoside diphosphates by a ping-pong mechanism involving the formation of a high energy phospho-histidine intermediate [1, 2]. Besides their known functions in the control of intracellular nucleotide homeostasis, they are involved in multiple physiological and pathological cellular processes such as differentiation, development, metastastic dissemination or cilia functions. Over the past 15 years, ten human genes have been discovered encoding partial, full length, and/or tandemly repeated Nm23/NDPK domains, with or without N-or C-terminal extensions and/or additional domains. These genes encode proteins exhibiting different functions at various tissular and subcellular localizations. Most of these genes appear late in evolution with the emergence of the vertebrate lineage. This review summarizes the present knowledge on these multitalented proteins.

Published
2009
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18. Interaction of NDPK-D with cardiolipin-containing membranes: Structural basis and implications for mitochondrial physiology

Author

Malgorzata Tokarska-Schlattner, Raquel F. Epand, Marie-Lise Lacombe, Uwe Schlattner, Richard M. Epand, Mathieu Boissan, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], and Hamant, Sarah

Subjects
Models, Molecular, Cardiolipins, Protein Conformation, Translocase of the outer membrane, 7. Clean energy, Biochemistry, 03 medical and health sciences, Mitochondrial membrane transport protein, chemistry.chemical_compound, 0302 clinical medicine, Cardiolipin, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Inner mitochondrial membrane, 030304 developmental biology, 0303 health sciences, biology, Nucleoside Diphosphate Kinase D, Membrane Proteins, General Medicine, Intracellular Membranes, NM23 Nucleoside Diphosphate Kinases, Surface Plasmon Resonance, Mitochondrial carrier, Cell biology, Mitochondria, chemistry, Translocase of the inner membrane, biology.protein, DNAJA3, ATP–ADP translocase, 030217 neurology & neurosurgery, Protein Binding
Abstract

International audience; Nucleoside diphosphate kinases (NDPKs/Nm23), responsible for intracellular di- and tri-phosphonucleoside homeostasis, play multi-faceted roles in cellular energetic, signaling, proliferation, differentiation and tumor invasion. The mitochondrial NDPK-D, the NME4 gene product, is a peripheral protein of the inner membrane. Several new aspects of the interaction of NDPK-D with the inner mitochondrial membrane have been recently characterized. Surface plasmon resonance analysis using recombinant NDPK-D and different phospholipid liposomes showed that NDPK-D interacts electrostatically with anionic phospholipids, with highest affinity observed for cardiolipin, a phospholipid located mostly in the mitochondrial inner membrane. Mutation of the central arginine (R90) in a surface exposed cationic RRK motif unique to NDPK-D strongly reduced phospholipid interaction in vitro and in vivo. Stable expression of NDPK-D proteins in HeLa cells naturally almost devoid of this isoform revealed a tight functional coupling of NDPK-D with oxidative phosphorylation that depends on the membrane-bound state of the enzyme. Owing to its symmetrical hexameric structure exposing membrane binding motifs on two opposite sides, NDPK-D could bridge liposomes containing anionic phospholipids and promote lipid transfer between them. In vivo, NDPK-D could induce intermembrane contacts and facilitate lipid movements between mitochondrial membranes. Most of these properties are reminiscent to those of the mitochondrial creatine kinase. We review here the common properties of both kinases and we discuss their potential roles in mitochondrial functions such as energy production, apoptosis and mitochondrial dynamics.

Published
2009
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19. The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration

Author

Marie-Lise Lacombe, Christiane Mailleau, Malgorzata Tokarska-Schlattner, Caroline Borot, Oliver Speer, Uwe Schlattner, Mathieu Boissan, Annie Munier, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, Université Paris Diderot - Paris 7 (UPD7), Department of Biology, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Institute of Cell Biology, Hamant, Sarah, University of Zurich, and Schlattner, U

Subjects
Male, 1303 Biochemistry, MESH: Sequence Homology, Amino Acid, Mitochondrial intermembrane space, Mitochondria, Liver, MESH: Amino Acid Sequence, Mitochondrion, Biochemistry, 1307 Cell Biology, chemistry.chemical_compound, 0302 clinical medicine, Cardiolipin, MESH: Animals, MESH: Oxygen Consumption, Inner mitochondrial membrane, Nucleoside Diphosphate Kinase D, 0303 health sciences, Peripheral membrane protein, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Mitochondria, Cell biology, Metabolism and Bioenergetics, MESH: Intracellular Membranes, 030220 oncology & carcinogenesis, MESH: Mitochondria, Liver, MESH: Rats, Cardiolipins, MESH: Mitochondria, Molecular Sequence Data, 610 Medicine & health, Biology, 03 medical and health sciences, Oxygen Consumption, 1312 Molecular Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Inner membrane, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Rats, Wistar, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, Intracellular Membranes, MESH: Rats, Wistar, Cell Biology, MESH: Male, Rats, chemistry, 10036 Medical Clinic, MESH: NM23 Nucleoside Diphosphate Kinases, MESH: Cardiolipins
Abstract

International audience; Nucleoside diphosphate kinase (NDPK/Nm23), responsible for intracellular di- and triphosphonucleoside homeostasis, plays multiple roles in cellular energetics, signaling, proliferation, differentiation and tumor invasion. The only human NDPK with a mitochondrial targeting sequence is NDPK-D, the NME4 gene product, which is a peripheral protein of mitochondrial membranes. Subfractionation of rat liver and HEK 293 cell mitochondria revealed that NDPK-D is essentially bound to the inner membrane. Surface plasmon resonance analysis of the interaction using recombinant NDPK-D and model liposomes showed that NDPK-D interacts electrostatically with anionic phospholipids, with highest affinity observed for cardiolipin. Mutation of the central arginine (Arg-90) in a surface-exposed basic RRK motif unique to NDPK-D strongly reduced interaction with anionic phospholipids. Due to its symmetrical hexameric structure, NDPK-D was able to cross-link anionic phospholipid-containing liposomes, suggesting that NDPK-D could promote intermembrane contacts. Latency assays with isolated mitochondria and antibody binding to mitoplasts indicated a dual orientation for NDPK-D. In HeLa cells, stable expression of wild type but not of the R90D mutant led to membrane-bound enzyme in vivo. Respiration was significantly stimulated by the NDPK substrate TDP in mitochondria containing wild-type NDPK-D, but not in those expressing the R90D mutant, which is catalytically equally active. This indicates local ADP regeneration in the mitochondrial intermembrane space and a tight functional coupling of NDPK-D with oxidative phosphorylation that depends on its membrane-bound state.

Published
2008
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20. Externalization of Cardiolipin as an 'Eat-Me' Mitophageal Signal is Facilitated by NDPK-D

Author

Zhentai Huang, Yulia Y. Tyurina, Mathieu Boissan, Uwe Schlattner, Malgorzata Tokarska-Schlattner, Marie-Lise Lacombe, Raquel F. Epand, Richard M. Epand, Jianfei Jiang, Valerian E. Kagan, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], FRM (DPM20121125557), NIH U19AIO6802, and Fulbright scholarship program (VEK)

Subjects
0303 health sciences, Kinase, [SDV]Life Sciences [q-bio], Biophysics, Oxidative phosphorylation, Mitochondrion, Biology, Nucleoside-diphosphate kinase, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Biochemistry, Mitophagy, biology.protein, Cardiolipin, Translocase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Intermembrane space, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Mitochondria are vulnerable to damage, particularly by oxidative stress-induced injury imposed by many genetic and environmental factors. These malfunctioning mitochondria have to be eliminated to prevent an increasing generation of reactive oxygen species (ROS) that could trigger cell injury and death. This selective elimination of damaged mitochondria is executed via initiation of a specific type of mitochondrial autophagy - mitophagy. Our previous work has established that a mitochondria-specific phospholipid, cardiolipin (CL) - normally asymmetrically distributed between the mitochondrial inner (IMM) and outer (OMM) membranes - undergoes translocation to the OMM where it becomes externalized to the mitochondrial surface. This externalized CL serves as recognition signal for the autophageal machinery leading to the elimination of these mitochondria. The recognition is achieved through the selective binding of externalized CL with microtubule-associated protein light chain 3 (LC3). The mechanisms driving CL redistribution/externalization remain unknown. By using LC-MS analysis of mono-lyso-cardiolipins (mL-CL) formed by phospholipase A2 exogenously added and impermeable to mitochondria, we established that treatment of HeLa cells with a protonophoric uncoupler, CCCP, triggers mitophagy of depolarized mitochondria accompanied by CL externalization. We further found that CL externalization is dependent on an intermembrane space enzyme, nucleoside diphosphate kinase, NDPK-D. The latter, upon interaction with CL, loses its kinase function and turns into a CL-translocase. CL externalization and mitophagy were stimulated by transfecting HeLa cells with w/type but not mutant R90A NDPK-D, incapable of CL binding. Identification of NDPK-D as a pro-mitophageal CL translocase may be used in drug discovery paradigms for regulation of “mitochondrial health.” Supported by NIH U19AIO6802, Fondation pour la Recherche Medicale France (US, DPM20121125557) and Fulbright scholarship program (VEK).

Published
2014
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21. Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice

Author

Colette Rey, Chantal Housset, Elisabeth Lasnier, Axelle Cadoret, Dominique Wendum, Thomas Braescu, Silvia Zúñiga, Nicolas Chignard, Thomas Falguières, Mathieu Boissan, Dominique Rainteau, Delphine Firrincieli, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Molecular Sequence Data, Calcitriol receptor, Cell junction, digestive system, 03 medical and health sciences, Mice, 0302 clinical medicine, Cholestasis, Internal medicine, medicine, Animals, Amino Acid Sequence, Receptor, Biliary Tract, Ligation, 030304 developmental biology, Liver injury, Mice, Knockout, 0303 health sciences, Hepatology, biology, Bile duct, Calpain, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Epithelial Cells, medicine.disease, Cadherins, ErbB Receptors, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Intercellular Junctions, Autoimmune, Cholestatic and Biliary Disease, Liver, Biliary tract, biology.protein, Receptors, Calcitriol, 030211 gastroenterology & hepatology, Bile Ducts
Abstract

Alterations in apical junctional complexes (AJCs) have been reported in genetic or acquired biliary diseases. The vitamin D nuclear receptor (VDR), predominantly expressed in biliary epithelial cells in the liver, has been shown to regulate AJCs. The aim of our study was thus to investigate the role of VDR in the maintenance of bile duct integrity in mice challenged with biliary-type liver injury. Vdr−/− mice subjected to bile duct ligation (BDL) displayed increased liver damage compared to wildtype BDL mice. Adaptation to cholestasis, ascertained by expression of genes involved in bile acid metabolism and tissue repair, was limited in Vdr−/− BDL mice. Furthermore, evaluation of Vdr−/− BDL mouse liver tissue sections indicated altered E-cadherin staining associated with increased bile duct rupture. Total liver protein analysis revealed that a truncated form of E-cadherin was present in higher amounts in Vdr−/− mice subjected to BDL compared to wildtype BDL mice. Truncated E-cadherin was also associated with loss of cell adhesion in biliary epithelial cells silenced for VDR. In these cells, E-cadherin cleavage occurred together with calpain 1 activation and was prevented by the silencing of calpain 1. Furthermore, VDR deficiency led to the activation of the epidermal growth factor receptor (EGFR) pathway, while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells. Finally, truncation of E-cadherin was blunted when EGFR signaling was inhibited in VDR-silenced cells. Conclusion: Biliary-type liver injury is exacerbated in Vdr−/− mice by limited adaptive response and increased bile duct rupture. These results indicate that loss of VDR restricts the adaptation to cholestasis and diminishes bile duct integrity in the setting of biliary-type liver injury. (Hepatology 2013;58:1401–1412)

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