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Biomedical subjects

C Tournier

Publications and source records attributed to C Tournier.

At least 19 recordsLinked to original sources
PubMed2006

Total disc arthroplasty: consequences for sagittal balance and lumbar spine movement.

This in vivo biomechanical study was undertaken to analyze the consequences for sagittal balance and lumbar spine movement in three different lumbar disc prostheses. A total of 105 patients underwent total disc replacement in three different centers. The Maverick prosthesis was used in 46 patients, the SB Charité device was used in 49 patients and the Prodisc device was utilized in 10 patients. The analysis was computer assisted, using Spineview and Matlab softwares. The intra and inter-observer reliability and measurement uncertainty was performed. The analysis of lateral X-ray films in flexion-extension allowed to measure the prosthesis positioning, the range of motion (ROM), the localization of the mean center of rotation (MCR), the vertebral translation and the disc height, for each prosthesis device. The sagittal balance was analyzed on a full spine film. The parameters studied were described by Duval-Beaupère. The results were compared to the data found in literature, and compared to 18 asymptomatic volunteers, and 61 asymptomatic subjects, concerning the sagittal balance. The prostheses allowed an improvement of the ROM of less than 2 degrees. The ROM of L5-S1 prostheses ranged from 11.6 to 15.6% of the total lumbar motion during flexion-extension. At L4-L5 level, the ROM decreased when there was an arthrodesis associated at the L5-S1 level. There was no difference of ROM between the three prostheses devices. The MCR was linked to the ROM, but did not depend on the prosthesis offcentering. The disc height improved for any prosthesis, and decreased in flexion or in extension, when the prosthesis was offcentered. An increase of translation indicated a minor increase of the ROM at L4-L5 level after Maverick or SB Charité implantation. The L5-S1 arthrodesis was linked with an increase of the pelvic tilt. The lumbar lordosis curvature increased between L4 and S1, even more when a prosthesis was placed at the L3-L4 level. Total disc arthroplasty is useful in the surgical management of discogenic spinal pathology. The three prostheses studied allowed to retorate the disc height, the ROM, without disrupting the sagittal balance, but induced modification of the lumbar curvature.

Arthroplasty, Replacement↗
PubMed2006

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress.

Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5- or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5-/- and mek5-/- fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.

Animals↗
PubMed2001

MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines.

Mitogen-activated protein kinases (MAPK) are activated by phosphorylation on Thr and Tyr by MAPK kinases. Two MAPK kinases (MKK4 and MKK7) can activate the c-Jun NH(2)-terminal kinase (JNK) group of MAPK in vitro. JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. Targeted gene-disruption studies in mice were performed to examine the role of MKK4 and MKK7 in vivo. Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress. In contrast, disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines. These data demonstrate that MKK4 and MKK7 serve different functions in the JNK signal transduction pathway.

Animals↗
PubMed2001

Evolution of the composition of a selected bitter Camembert cheese during ripening: release and migration of taste-active compounds.

The aim of this study was to add to the understanding of changes in taste that occur during the ripening of a bitter Camembert cheese by the evolution of its composition. Physicochemical analyses were performed on rind, under-rind, and center portions of a Camembert cheese selected for its intense bitterness. At each of the six steps of ripening studied organic acids, sugars, total nitrogen, soluble nitrogen, phosphotungstic acid soluble nitrogen, non-protein nitrogen, Na, K, Ca, Mg, Pi, Cl, and biogenic amines were quantified in each portion. Changes in cheese composition seemed to mainly result from the development of Penicillium camemberti on the cheese outer layer. Migration phenomena and the release of potentially taste-active compounds allowed for the evolution of saltiness, sourness, and bitterness throughout ripening to be better understood. Apart from taste-active compounds, the impact of the cheese matrix on its taste development is discussed.

Carbohydrates↗
PubMed2000

Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway.

The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.

Animals↗
PubMed2000

JNK is required for effector T-cell function but not for T-cell activation.

The hallmark of T-cell activation is the production of interleukin 2 (IL-2). c-Jun amino-terminal kinase (JNK), a MAP kinase that phosphorylates c-Jun and other components of the AP-1 group of transcription factors, has been implicated in the activation of IL-2 expression. Previously, we found that T cells from mice deficient in the Jnk1 or Jnk2 gene can be activated and produce IL-2 normally, but are deficient in functional differentiation into Th1 or Th2 subsets. However, studies of mice with compound mutations indicate that JNK1 and JNK2 are redundant during mouse development. Here we use three new mouse models in which peripheral T cells completely lack JNK proteins or signalling, to test whether the JNK signalling pathway is crucial for IL-2 expression and T-cell activation. Unexpectedly, these T cells made more IL-2 and proliferated better than wild-type cells. However, production of effector T-cell cytokines did require JNK. Thus, JNK is necessary for T-cell differentiation but not for naive T-cell activation.

Animals↗
PubMed1999

Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation.

The molecular basis for restricted cytokine expression by T helper 1 (Th1) and T helper 2 (Th2) cells is unclear. Previous studies found that P1, an element of the interleukin 4 (IL-4) promoter that binds AP-1, is important for Th2-restricted IL-4 expression. Here we show that JunB, but not the other Jun family members, was selectively induced in Th2 cells and not in Th1 cells during differentiation. JunB has previously been considered to be a negative regulator of transcription. However, we show that JunB binds directly to the P1 site and synergizes with c-Maf to activate an IL-4 luciferase reporter gene. JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. In transgenic mice, elevated JunB levels caused increased expression of several Th2 cytokines in developing Th1 cells. JunB also upregulated IL-4 expression in response to immunization. Thus, the early increase of JunB protein in Th2 cells can provide the specificity for c-Maf in IL-4 expression during T cell development and directs thereby Th2 differentiation.

Animals↗
PubMed1999

Molecular basis of T-cell differentiation.

In summary, a multitude of regulatory systems are employed to cause the selective activation of target cytokine genes in Th1 and Th2 effector cells. These mechanisms involve both positive and negative regulation and employ at least three kinds of mechanisms. In the first, selective expression of transcription factors such as GATA3 in Th2 cells and the homeobox gene HLX in Th1 cells occurs, and appears in both cases to play a causal role. Another example of this would be c-maf, discovered by the Glimcher laboratory. A second mechanism is by the selective accumulation of protein through posttranscriptional mechanisms. Thus, junB accumulates in Th2 cells despite the fact that the junB mRNA levels are not different between Th1 and Th2 cells. Finally, the selective use of signaling pathways, in the case studied here MAP kinase pathways, leads to the selective activation of target genes. We believe that transcriptional up-regulation of rac2 leads to the coupling of both the p38 and JNK MAP kinase pathways to the T-cell receptor and/or costimulatory receptors, thereby providing a lineage-specific signal.

Cell Differentiation↗
PubMed1999

The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases.

The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (alpha, beta, and gamma isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7alpha isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7alpha isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7beta and MKK7gamma isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that the MKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

Alternative Splicing↗
PubMed1998

A mammalian scaffold complex that selectively mediates MAP kinase activation.

The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by the exposure of cells to multiple forms of stress. A putative scaffold protein was identified that interacts with multiple components of the JNK signaling pathway, including the mixed-lineage group of MAP kinase kinase kinases (MLK), the MAP kinase kinase MKK7, and the MAP kinase JNK. This scaffold protein selectively enhanced JNK activation by the MLK signaling pathway. These data establish that a mammalian scaffold protein can mediate activation of a MAP kinase signaling pathway.

Animals↗
PubMed1997

Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase.

The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by phosphorylation on Thr and Tyr. Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK. In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway. MKK7 is therefore established to be a novel component of the JNK signal transduction pathway.

Amino Acid Sequence↗
PubMed1997

Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity.

MKK4 is a member of the mitogen-activated protein kinase kinase group of dual specificity protein kinases that functions as an activator of the c-Jun NH2-terminal kinase (JNK) in vitro. To examine the function of MKK4 in vivo, we investigated the effect of targeted disruption of the MKK4 gene. Crosses of heterozygous MKK4 (+/-) mice demonstrated that homozygous knockout (-/-) animals die before embryonic day 14, indicating that the MKK4 gene is required for viability. The role of MKK4 in JNK activation was examined by investigation of cultured MKK4 (+/+) and MKK4 (-/-) cells. Disruption of the MKK4 gene blocked JNK activation caused by: (i) the mitogen-activated protein kinase kinase kinase MEKK1, and (ii) treatment with anisomycin or heat shock. In contrast, JNK activation caused by other forms of environmental stress (UV-C radiation and osmotic shock) was partially inhibited in MKK4 (-/-) cells. Regulated AP-1 transcriptional activity, a target of the JNK signal transduction pathway, was also selectively blocked in MKK4 (-/-) cells. Complementation studies demonstrated that the defective AP-1 transcriptional activity was restored by transfection of MKK4 (-/-) cells with an MKK4 expression vector. These data establish that MKK4 is a JNK activator in vivo and demonstrate that MKK4 is an essential component of the JNK signal transduction pathway.

Animals↗
PubMed1997

Mediation by arachidonic acid metabolites of the H2O2-induced stimulation of mitogen-activated protein kinases (extracellular-signal-regulated kinase and c-Jun NH2-terminal kinase).

Reactive oxygen species modulate major cellular functions by mechanisms which are still poorly understood. Recently, H2O2 has been reported to stimulate the activity of the mitogen-activated protein kinases (MAPKs) ERK and JNK, and the expression of the proto-oncogenes c-fos and c-jun. As their expression is enhanced by H2O2 in astrocytes, we studied whether these MAPKs were stimulated by H2O2 in primary cultured astrocytes. The result was positive, a maximum of stimulation being reached with 200 microM H2O2 (0.3 pmol H2O2/cell) for both ERK and JNK. ERK was previously reported to stimulate cytosolic phospholipase A2 phosphorylation and activity. H2O2 stimulated the release of arachidonic acid in astrocytes, as already reported in other cell types. We found also that cPLA2 phosphorylation was increased by H2O2. Moreover, the stimulation by H2O2 of ERK and JNK was decreased by phospholipase A2 activity inhibitors. When astrocytes were incubated first with eicosatetraynoic acid, a structural analogue competing in arachidonic acid metabolism, the stimulation of JNK by H2O was also inhibited, suggesting the involvement of arachidonic acid metabolites. Cyclooxygenase or cytochrome P450 monooxygenase inhibitors failed in decreasing the MAPK stimulation by H2O2, whereas lipoxygenase inhibitors completely abolished that of JNK. Mitogenicity has been reported to be stimulated by H2O2 in other cell types. Although ERK was strongly and durably stimulated by 200 microM H2O2 in astrocytes, at the same extent as by mitogenic growth factors, basal thymidine incorporation rate was decreased by more than 80% after 12-15 h. Moreover, the stimulation of thymidine incorporation induced by basic fibroblast growth factor was transiently abolished by H2O2. Furthermore, H2O2 likely induced the expression of CL100/PAC1/MKP-1, a dual specificity phosphatase which has been implicated in ERK and JNK inactivation in the nucleus. Finally, the prior treatment of astrocytes with MK886, a 5-lipoxygenase-activating protein inhibitor, prevented JNK from stimulation, but did not prevent thymidine incorporation from inhibition, both induced by H2O2. These results strongly suggest an involvement of arachidonic acid and/or its metabolites in the stimulation of both ERK and JNK following the oxidative stress evoked by H2O2, which induced a cell cycle arrest probably independent of the stimulation of JNK.

Animals↗
PubMed1995

Stimulation of mitogen-activated protein kinase by thyrotropin in primary cultured human thyroid follicles.

In the thyroid, thyrotropin (TSH) stimulates both growth and function, and stimulates the production of cAMP which reproduces most of the effects of TSH. Here, we report evidence that TSH stimulates the mitogen-activated protein (MAP) kinase cascade through a cAMP-independent pathway, in human thyroid. TSH stimulated MAP kinase activity (4-9-fold the basal level) measured in the cytosolic fractions of primary cultured thyroid follicles. Maximal activity was reached after 20 min and remained sustained for 1-3 h, TSH being as potent as EGF; EC50 was 1.5 nM TSH. Only a single isoform of MAP kinase (p42) was detected in the follicles. p42 was phosphorylated on tyrosine residues and showed a reduced electrophoretic mobility in follicles stimulated by TSH. All these effects on MAP kinase were decreased by preincubation of the follicles with human anti-TSH receptor antibodies. The stimulation of MAP kinase by TSH was neither blocked by pertussis toxin nor reproduced by forskolin, cholera toxin, or 8-bromo-cAMP. In conclusion, in human thyroid cells, in contrast with previous observations on dog thyroid cells, TSH stimulates strongly MAP kinase through a pertussis toxin-insensitive and cAMP-independent pathway.

Amino Acid Sequence↗
PubMed1995

Stimulation of mitogen-activated protein kinase by thyrotropin in astrocytes.

We have recently reported the expression of the thyrotropin (TSH) receptor and the stimulation by TSH of type-II iodothyronine 5'-deiodinase in astrocytes. In these cells, TSH stimulated arachidonate release, but neither cAMP production, nor phosphatidylinositolbisphosphate hydrolysis, as described in the human thyroid gland. Here we report, in contrast to a recent observation made in dog thyroid cells, that TSH stimulates mitogen-activated protein kinase (MAP kinase) in astrocytes. Indeed, TSH increases the tyrosine phosphorylation of the two isoforms of MAP kinase expressed in these cells, in correlation with both a slower electrophoretic migration of the tyrosine phosphorylated species and an enhanced enzymic activity measured on a specific substrate peptide. This stimulation of MAP kinase by TSH was specifically inhibited by incubation of astrocytes in the presence of human blocking anti-(TSH receptor) IgG, and by immunoprecipitation of TSH with monoclonal anti-TSH IgG. In astrocytes, TSH was neither mitogenic by itself, nor modified significantly the basic-fibroblast-growth-factor-induced mitogenesis. The stimulation of MAP kinase by TSH was not affected by treatment with pertussis toxin, suggesting guanine-nucleotide-binding-regulatory protein i/o was not implicated in this TSH effect. Our model will allow the study of the stimulation of MAP kinase by TSH without interference either from cAMP or from phosphoinositide signalling pathways.

Animals↗
PubMed1994

MAP kinase cascade in astrocytes.

We have studied in cultured rat astroglial cells MAP kinases, known for their role in intracellular signal transduction. The MAP kinase activity was stimulated by growth factors (FGFb, FGFa, EGF, PDGF, and IGF1), by a phorbol ester (TPA) activating-protein kinase C (PKC), by a neuropeptide (endothelin-1), and by a neuromediator (carbachol). Astrocytes pretreated for 18 h with TPA were still stimulated by growth factors and endothelin, suggesting that down-regulated isoforms of PKC are not involved in MAP kinase activation. In contrast, the small effect of carbachol was suppressed by TPA pretreatment. Astrocytes contained two proteins (p41 and p44) recognized by MAP kinase antibody. These proteins were phosphorylated on tyrosine residues in the cytosols of stimulated astrocytes. The kinetics of MAP kinase activation by FGFb and IGF1 were very different. FGFb promoted a rapid activation of MAP kinase (about 10 min) plus a prolonged phase that lasted at least 12 h. IGF1 produced only a rapid transient peak of activation at about 20 min. Hence, extracellular signals might generate different effects in astrocytes by differentially modulating the MAP kinase cascade. On a Mono Q column the growth factor-stimulated MAP kinase activity was separated into two peaks containing p41 and p44. Stimulation of astrocytes altered the elution pattern of p44 as a result of its phosphorylation. An ATP-dependent MAP kinase activator (MW = 40-45 kDa) was found in fractions of FGFb-stimulated cells which were not retained on Mono Q column, indicating the existence of a MAP kinase kinase (MEK) in astrocytes. C-Raf, identified in other cells as a MAP kinase kinase kinase, was also present in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗