Marie-Clotilde Alves-Guerra

Publications (13)66.59 Total impact

• Article: Analysis of uncoupling protein 2-deficient mice upon anaesthesia and sedation revealed a role for UCP2 in locomotion.

  Marie-Clotilde Alves-Guerra, Caroline Aheng, Claire Pecqueur, Sandrine Masscheleyn, Pierre Louis Tharaux, Anne Druilhe, Daniel Ricquier, Etienne Challet, Bruno Miroux
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  ABSTRACT: General anaesthesia is associated with hypothermia, oxidative stress, and immune depression. Uncoupling Protein (UCP2) is a member of the mitochondrial carrier family present in many organs including the spleen, the lung and the brain. A role of UCP2 in the activation of the inflammatory/immune cells, in the secretion of hormones, and in the excitability of neurons by regulating the production of reactive oxygen species has been discussed. Because of the side effects of anaesthesia listed above, we aimed to question the expression and the function of UCP2 during anaesthesia. Induction of anaesthesia with ketamine (20 mg/kg) or isoflurane (3.6%) and induction of sedation with the α2 adrenergic receptor agonist medetomidine (0.2 mg/kg) stimulated infiltration of immune cells in the lung and increased UCP2 protein content in the lung, in both immune and non-immune cells. UCP2 content in the lung inversely correlated with body temperature decrease induced by medetomidine treatment. Challenge of the Ucp2(-/-) mice with isoflurane and medetomidine revealed an earlier behavioral recovery phenotype. Transponder analysis of body temperature and activity showed no difference between Ucp2(-/-) and control mice in basal conditions. However, upon an acute decrease of body temperature induced by medetomidine, Ucp2(-/-) mice exhibited increased locomotion activity. Together, these results show that UCP2 is rapidly mobilized during anaesthesia and sedation in immune cells, and suggest a role of UCP2 in locomotion.
  PLoS ONE 01/2012; 7(8):e41846. · 4.09 Impact Factor
• Article: Assembly of a Notch transcriptional activation complex requires multimerization.

  Rodrigo Vasquez-Del Carpio, Fred M Kaplan, Kelly L Weaver, Jeffrey D VanWye, Marie-Clotilde Alves-Guerra, David J Robbins, Anthony J Capobianco
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  ABSTRACT: Notch transmembrane receptors direct essential cellular processes, such as proliferation and differentiation, through direct cell-to-cell interactions. Inappropriate release of the intracellular domain of Notch (N(ICD)) from the plasma membrane results in the accumulation of deregulated nuclear N(ICD) that has been linked to human cancers, notably T-cell acute lymphoblastic leukemia (T-ALL). Nuclear N(ICD) forms a transcriptional activation complex by interacting with the coactivator protein Mastermind-like 1 and the DNA binding protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene expression. Although it is well understood that N(ICD) forms a transcriptional activation complex, little is known about how the complex is assembled. In this study, we demonstrate that N(ICD) multimerizes and that these multimers function as precursors for the stepwise assembly of the Notch activation complex. Importantly, we demonstrate that the assembly is mediated by N(ICD) multimers interacting with Skip and Mastermind. These interactions form a preactivation complex that is then resolved by CSL to form the Notch transcriptional activation complex on DNA.
  Molecular and cellular biology 01/2011; 31(7):1396-408. · 6.06 Impact Factor
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  Available from: PubMed Central

  Article: Deletion of UCP2 in iNOS deficient mice reduces the severity of the disease during experimental autoimmune encephalomyelitis.

  Caroline Aheng, Nathalie Ly, Mairead Kelly, Saleh Ibrahim, Daniel Ricquier, Marie-Clotilde Alves-Guerra, Bruno Miroux
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  ABSTRACT: Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2-/- mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/-0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos-/- mice.
  PLoS ONE 01/2011; 6(8):e22841. · 4.09 Impact Factor
• Article: Mastermind-like 1 Is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival.

  Marie-Clotilde Alves-Guerra, Chiara Ronchini, Anthony J Capobianco
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  ABSTRACT: Misregulation of the Wnt signaling pathway has been linked to many human cancers including colon carcinoma and melanoma. The primary mediator of the oncogenic effects of the Wnt signaling pathway is beta-catenin. Accumulation of nuclear beta-catenin and transcription activation of lymphoid enhancer factor 1 (LEF1)/T-cell factor (TCF) target genes underlie the oncogenic activity. However, the mechanism of beta-catenin-mediated transcriptional activation remains poorly understood. In this study, we identified Mastermind-like 1 (Maml1), which is thought to be a specific coactivator for the Notch pathway, as a coactivator for beta-catenin. We found that Maml1 participates in the Wnt signaling by modulating the beta-catenin/TCF activity. We show in vivo that Maml1 is recruited by beta-catenin on the cyclin D1 and c-Myc promoters. Importantly, we show that Maml1 functions in the Wnt/beta-catenin pathway independently of Notch signaling. Finally, we show that the knockdown of Mastermind-like family proteins in colonic carcinoma cells results in cell death by affecting beta-catenin-induced expression of cyclin D1 and c-Myc. This is the first demonstration of a role for the Mastermind-like family in another signaling pathway and that the knockdown of Mastermind-like family function leads to tumor cell death.
  Cancer Research 10/2007; 67(18):8690-8. · 7.86 Impact Factor
• Article: Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels.

  Fabienne de Bilbao, Denis Arsenijevic, Philippe Vallet, Ole Petter Hjelle, Ole Petter Ottersen, Constantin Bouras, Yvette Raffin, Karin Abou, Wolfgang Langhans, Sheila Collins, Julie Plamondon, Marie-Clotilde Alves-Guerra, Anne Haguenauer, Irene Garcia, Denis Richard, Daniel Ricquier, Panteleimon Giannakopoulos
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  ABSTRACT: Uncoupling protein 2 (UCP2) is suggested to be a regulator of reactive oxygen species production in mitochondria. We performed a detailed study of brain injury, including regional and cellular distribution of UCP2 mRNA, as well as measures of oxidative stress markers following permanent middle cerebral artery occlusion in UCP2 knockout (KO) and wild-type (WT) mice. Three days post ischemia, there was a massive induction of UCP2 mRNA confined to microglia in the peri-infarct area of WT mice. KO mice were less sensitive to ischemia as assessed by reduced brain infarct size, decreased densities of deoxyuridine triphosphate nick end-labelling (TUNEL)-labelled cells in the peri-infact area and lower levels of lipid peroxidation compared with WT mice. This resistance may be related to the substantial increase of basal manganese superoxide dismutase levels in neurons of KO mice. Importantly, we found a specific decrease of mitochondrial glutathione (GSH) levels in UCP2 expressing microglia of WT, but not in KO mice after ischemia. This specific association between UCP2 and mitochondrial GSH levels regulation was further confirmed using lipopolysaccharide models of peripheral inflammation, and in purified peritoneal macrophages. Moreover, our data imply that UCP2 is not directly involved in the regulation of ROS production but acts by regulating mitochondrial GSH levels in microglia.
  Journal of Neurochemistry 07/2004; 89(5):1283-92. · 4.06 Impact Factor
• Article: The biology of mitochondrial uncoupling proteins.

  Sophie Rousset, Marie-Clotilde Alves-Guerra, Julien Mozo, Bruno Miroux, Anne-Marie Cassard-Doulcier, Frédéric Bouillaud, Daniel Ricquier
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  ABSTRACT: Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria. They are found in all mammals and in plants. They belong to the family of anion mitochondrial carriers including adenine nucleotide transporters. The term "uncoupling protein" was originally used for UCP1, which is uniquely present in mitochondria of brown adipocytes, the thermogenic cells that maintain body temperature in small rodents. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP synthase. Activation of UCP1 enhances respiration, and the uncoupling process results in a futile cycle and dissipation of oxidation energy as heat. UCP2 is ubiquitous and highly expressed in the lymphoid system, macrophages, and pancreatic islets. UCP3 is mainly expressed in skeletal muscles. In comparison to the established uncoupling and thermogenic activities of UCP1, UCP2 and UCP3 appear to be involved in the limitation of free radical levels in cells rather than in physiological uncoupling and thermogenesis. Moreover, UCP2 is a regulator of insulin secretion and UCP3 is involved in fatty acid metabolism.
  Diabetes 03/2004; 53 Suppl 1:S130-5. · 8.29 Impact Factor
• Article: Uncoupling protein 2, but not uncoupling protein 1, is expressed in the female mouse reproductive tract.

  Sophie Rousset, Marie-Clotilde Alves-Guerra, Salma Ouadghiri-Bencherif, Leslie P Kozak, Bruno Miroux, Denis Richard, Frédéric Bouillaud, Daniel Ricquier, Anne-Marie Cassard-Doulcier
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  ABSTRACT: Uncoupling proteins (UCPs) are transporters of the inner mitochondrial membrane. Whereas UCP1 is uniquely present in brown adipose tissue where it uncouples respiration from ATP synthesis and activates respiration and heat production, UCP2 is present in numerous tissues, and its exact function remains to be clarified. Two sets of data provided the rationale for this study: (i) the intriguing report that UCP1 is present in uterus of mice (Nibbelink, M., Moulin, K., Arnaud, E., Duval, C., Penicaud, L., and Casteilla, L. (2001) J. Biol. Chem. 276, 47291-47295); and (ii) an observation that Ucp2(-/-) female mice (homozygous matings) have smaller litters compared with Ucp2(+/+) animals (S. Rousset and A.-M. Cassard-Doulcier, unpublished observations). These data prompted us to examine the expression of UCP1 and UCP2 in the reproductive tract of female mice. Using wild type, Ucp1(-/-) mice, and Ucp2(-/-) mice, we were unable to detect UCP1 in uterus of mice with appropriate antibodies, and we conclude that the signal assigned to UCP1 by others was neither UCP1 nor UCP2. Using a polyclonal antibody against UCP2 and tissues from Ucp2(-/-) mice as controls, UCP2 was detected in ovary, oviduct, and uterus. Expression of Ucp2 mRNA was also observed in ovary and uterus using in situ hybridization analysis. Bone marrow transplantation experiments revealed that the UCP2 signal of the ovary was restricted to ovarian cells. UCP2 level in ovary decreased during follicular growth and increased during the pre-ovulatory period, during which aspects of an inflammatory process are known to exist. Because UCP2 down-regulates reactive oxygen species, a role in the regulation of inflammatory events linked to the preparation of ovulation is suggested.
  Journal of Biological Chemistry 12/2003; 278(46):45843-7. · 4.77 Impact Factor
• Article: Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation.

  Marie-Clotilde Alves-Guerra, Sophie Rousset, Claire Pecqueur, Ziad Mallat, Julie Blanc, Alain Tedgui, Fredéric Bouillaud, Anne-Marie Cassard-Doulcier, Daniel Ricquier, Bruno Miroux
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  ABSTRACT: The mitochondrial uncoupling protein 2 (UCP2) is expressed in spleen, lung, intestine, white adipose tissue, and immune cells. Bone marrow transplantation in mice was used to assess the contribution of immune cells to the expression of UCP2 in basal condition and during inflammation. Immune cells accounted for the total amount of UCP2 expression in the spleen, one-third of its expression in the lung, and did not participate in its expression in the intestine. LPS injection stimulated UCP2 expression in lung, spleen, and intestine in both immune and non-immune cells. Successive injections of LPS and dexamethasone or N-acetyl-cysteine prevented the induction of UCP2 in all three tissues, suggesting that oxygen free radical generation plays a role in UCP2 regulation. Finally, both previous studies and our data show that there is down-regulation of UCP2 in immune cells during their activation in the early stages of the LPS response followed by an up-regulation in UCP2 during the later stages to protect all cells against oxidative stress.
  Journal of Biological Chemistry 11/2003; 278(43):42307-12. · 4.77 Impact Factor
• Article: Pancreatic beta-cell lipotoxicity induced by overexpression of hormone-sensitive lipase.

  Maria Sörhede Winzell, Håkan Svensson, Sven Enerbäck, Kim Ravnskjaer, Susanne Mandrup, Victoria Esser, Peter Arner, Marie-Clotilde Alves-Guerra, Bruno Miroux, Frank Sundler, Bo Ahrén, Cecilia Holm
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  ABSTRACT: Lipid perturbations associated with triglyceride overstorage in beta-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in beta-cells, in the development of lipotoxicity, we generated transgenic mice overexpressing hormone-sensitive lipase specifically in beta-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased in transgenic compared with wild-type islets. This was reflected in significantly lower triglycerides levels in transgenic compared with wild-type islets in mice receiving the high-fat diet, whereas no difference in islet triglycerides was found between the two genotypes under low-fat diet conditions. Our results highlight the importance of mobilization of the islet triglyceride pool in the development of beta-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating beta-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid-activated transcription factors, which in turn alter the expression of critical genes. One such gene might be uncoupling protein-2, which was found to be upregulated in transgenic islets, a change that was accompanied by decreased ATP levels.
  Diabetes 09/2003; 52(8):2057-65. · 8.29 Impact Factor
• Article: No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria.

  Elodie Couplan, Maria del Mar Gonzalez-Barroso, Marie Clotilde Alves-Guerra, Daniel Ricquier, Marc Goubern, Frédéric Bouillaud
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  ABSTRACT: The phenotypes observed in mice whose uncoupling protein (Ucp2) gene had been invalidated by homologous recombination (Ucp2(-/-) mice) are consistent with an increase in mitochondrial membrane potential in macrophages and pancreatic beta cells. This could support an uncoupling (proton transport) activity of UCP2 in the inner mitochondrial membrane in vivo. We used mitochondria from lung or spleen, the two organs expressing the highest level of UCP2, to compare the proton leak of the mitochondrial inner membrane of wild-type and Ucp2(-/-) mice. No difference was observed under basal conditions. Previous reports have concluded that retinoic acid and superoxide activate proton transport by UCP2. Spleen mitochondria showed a higher sensitivity to retinoic acid than liver mitochondria, but this was not caused by UCP2. In contrast with a previous report, superoxide failed to increase the proton leak rate in kidney mitochondria, where no UCP2 expression was detected, and also in spleen mitochondria, which does not support stimulation of UCP2 uncoupling activity by superoxide. Finally, no increase in the ATP/ADP ratio was observed in spleen or lung of Ucp2(-/-) mice. Therefore, no evidence could be gathered for the uncoupling activity of the UCP2 present in spleen or lung mitochondria. Although this may be explained by difficulties with isolated mitochondria, it may also indicate that UCP2 has another physiological significance in spleen and lung.
  Journal of Biological Chemistry 08/2002; 277(29):26268-75. · 4.77 Impact Factor
• Article: Uncoupling Protein 2, in Vivo Distribution, Induction upon Oxidative Stress, and Evidence for Translational Regulation

  Claire Pecqueur, Marie-Clotilde Alves-Guerra, Chantal Gelly, Corinne Lévi-Meyrueis, Elodie Couplan, Sheila Collins, Daniel Ricquier, Frédéric Bouillaud, Bruno Miroux
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  ABSTRACT: Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier family and partially uncouples respiration from ATP synthesis when expressed in recombinant yeast mitochondria. We generated a highly sensitive polyclonal antibody against human UCP2. Its reactivity toward mitochondrial proteins was compared between wild type and ucp2(−/−) mice, leading to non-ambiguous identification of UCP2. We detected UCP2 in spleen, lung, stomach, and white adipose tissue. No UCP2 was detected in heart, skeletal muscle, liver, and brown adipose tissue. The level of UCP2 in spleen mitochondria is less than 1% of the level of UCP1 in brown adipose tissue mitochondria. Starvation and LPS treatments increase UCP2 level up to 12 times in lung and stomach, which supports the hypothesis that UCP2 responds to oxidative stress situations. Stimulation of the UCP2 expression occurs without any change in UCP2 mRNA levels. This is explained by translational regulation of the UCP2 mRNA. We have shown that an upstream open reading frame located in exon two of theucp2 gene strongly inhibits the expression of the protein. This further level of regulation of the ucp2 gene provides a mechanism by which expression can be strongly and rapidly induced under stress conditions.
  Journal of Biological Chemistry 03/2001; 276(12):8705-8712. · 4.77 Impact Factor
• Article: Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production

  Denis Arsenijevic, Hiroki Onuma, Claire Pecqueur, Serge Raimbault, Brian S. Manning, Bruno Miroux, Elodie Couplan, Marie-Clotilde Alves-Guerra, Marc Goubern, Richard Surwit, Fr|[eacute]|d|[eacute]|ric Bouillaud, Denis Richard, Sheila Collins, Daniel Ricquier
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  ABSTRACT: The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1−3). As Ucp2 is widely expressed in mammalian tissues4, 5, uncouples respiration6 and resides within a region of genetic linkage to obesity4, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages4, 5, 7, suggesting a role for Ucp2 in immunity or inflammatory responsiveness4. We investigated the response to infection with Toxoplasma gondii in Ucp2 -/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2 -/- mice (63% decrease, P<0.04). Macrophages from Ucp2 -/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
  Nature Genetics. 11/2000; 26(4):435-439.
• Article: Transcriptional Activation of the Human ucp1 Gene in a Rodent Cell Line

  Maria del Mar Gonzalez-Barroso, Claire Pecqueur, Chantal Gelly, Daniel Sanchis, Marie-Clotilde Alves-Guerra, Frederic Bouillaud, Daniel Ricquier, Anne-Marie Cassard-Doulcier
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  ABSTRACT: Uncoupling protein 1 (UCP1) is uniquely expressed in brown adipocytes and generates heat production by uncoupling respiration from ATP synthesis. The activatory effects of norepinephrine and retinoic acid (RA) on rodent ucp1gene transcription have been well characterized. These effects are mediated by a 211-base pair (bp) enhancer which is also sufficient to restrict expression to brown adipose tissue. The molecular mechanisms controlling the transcription of the human ucp1 gene are unknown. In order to study the transcriptional regulation of the human gene, we set up chloramphenicol acetyltransferase constructs containing the entire or deleted 5′ regions upstream of the transcriptional start site of the gene. These constructs were transiently transfected in a mouse cell line. A 350-bp hormone response region showing a significant homology with the rat ucp1 enhancer and located between theBclI polymorphic site and an AatII site (bp −3820/−3470) was detected. This region was sufficient to mediate the stimulation by RA and by combined treatments (RA + isoproterenol (ISO), RA + thiazolidinedione (TZD), or RA + ISO + TZD). The highest stimulation, a 26-fold increase in basal activity, was obtained by RA + ISO + TZD treatment. In contrast to the rodent gene, under our conditions, the effect of ISO and/or TZD is dependent on RA stimulation. Analysis of 105 bp inside the 350-bp element by site-directed mutagenesis and gel retardation experiments demonstrated that a multipartite response element mediates the drug stimulation. This region binds RARs and RXRs nuclear factors, CREB/ATF factors, and also PPARγ despite the absence of a consensus peroxisome-proliferator response element. The activation of the human ucp1 gene transcription by certain hormones or drugs, and the identification of the cis-elements involved, will help to identify new compounds activating fat oxidation and energy expenditure in humans.
  Journal of Biological Chemistry 10/2000; 275(41):31722-31732. · 4.77 Impact Factor