Hsp27 (HspB1) and αB-crystallin (HspB5) as therapeutic targets

AbstractHsp27 and αB-crystallin are molecular chaperones that are constitutively expressed in several mammalian cells, particularly in pathological conditions. These proteins share functions as diverse as protection against toxicity mediated by aberrantly folded proteins or oxidative-inflammation conditions. In addition, these proteins share anti-apoptotic properties and are tumorigenic when expressed in cancer cells. This review summarizes the current knowledge about Hsp27 and αB-crystallin and the implications, either positive or deleterious, of these proteins in pathologies such as neurodegenerative diseases, myopathies, asthma, cataracts and cancers. Approaches towards therapeutic strategies aimed at modulating the expression and/or the activities of Hsp27 and αB-crystallin are presented

Structure and evolution of the Gulf of Lions: The Sardinia seismic experiment and the GOLD (Gulf of Lions Drilling) project

International audienceThe study of the deep structure and evolution of passive continental margins is important for the understanding of rifting processes and the formation of associated sedimentary basins. Since the classical models of McKenzie (1978) and Wernicke (1985), understanding how passive continental margins form, that is to say mainly the way that continental lithosphere is thinned leading to subsidence, remains one of the main challenges in the Earth sciences. Many recent observations and discoveries have modified our basic views of margin formation. The conservational models paradigm (i.e., simple shear, pure shear, or polyphase models), which exclude exchanges between lower continental crust and upper mantle and which are usually proposed to explain lithospheric stretching and consequent crustal thinning of passive continental margins, fail to completely explain all these observations. Furthermore, these models imply a large amount of horizontal movement, movements not observed in the field. In consequence, new concepts need to be built and tested

Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy

: SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired

Knock Down of Heat Shock Protein 27 (HspB1) Induces Degradation of Several Putative Client Proteins

Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions

Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment

cIAPs keep RIP1 from getting to the DISC complex and complex II; when cIAPs are repressed, signaling is modulated by the cFLIP isoform

TAK1 Is Required for Survival of Mouse Fibroblasts Treated with TRAIL, and Does So by NF-κB Dependent Induction of cFLIPL

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a “death ligand”—a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-κB and JNK signalling pathways. To determine the role of TGF-β-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1−/− MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-κB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-κB, protected TAK1−/− MEFs against TRAIL killing, suggesting that TAK1 activation of NF-κB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-κB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK1−/− MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1–NF-κB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance

La clofarabine dans les leucémies aigües de l'enfant réfractaires ou en rechute (expérience niçoise)

Le pronostic des leucémies aigües (LA) réfractaires ou en rechute reste extrêmement péjoratif chez l enfant. La Clofarabine, nouvel analogue nucléosidique, est indiquée dans les LA de l enfant réfractaires ou en rechute après au moins deux lignes de traitement. L objectif de ce travail est de rapporter l'expérience de l'utilisation de la Clofarabine dans les LA de l enfant au sein du service d onco-hématologie pédiatrique de Nice tant en termes de tolérance que d efficacité. Nous avons réalisé une étude rétrospective sur une période de 4 ans des dossiers de tous les patients pris en charge pour une LA et traités par Clofarabine. Les données recueillies portaient sur le type de leucémie, les facteurs pronostiques associés, les traitements reçus avant la Clofarabine, la tolérance et l'efficacité ainsi que le devenir de ces patients. L efficacité de la Clofarabine était évaluée en fonction du taux de réponse global observé immédiatement après avoir bénéficié du traitement. Sur 7 patients inclus dans l étude : 5 patients ont reçu l association clofarabine/cyclophosphamide/étoposide sur une durée de 5 jours et 2 patients ont été traités par une bithérapie clofarabine/aracytine. Tous ont présenté au moins un effet secondaire mais avec une tolérance acceptable. Le taux de réponse global était de 86%. 6 patients ont pu bénéficier d une allogreffe de moelle. 3 patients (43%) sont actuellement en rémission. Malgré une petite cohorte, notre étude confirme l efficacité de la Clofarabine dans les LA réfractaires ou en rechute. La tolérance est acceptable et 86% des patients ont pu être greffés ce qui est l objectif en cas de maladie réfractaire. Ce traitement permet d obtenir une rémission chez des patients en échec des précédentes chimiothérapies. Les perspectives actuelles concernent l utilisation de la Clofarabine de manière plus précoce notamment dès la première rechute dans les leucémies du groupe haut risque.NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

South and Equatorial Atlantic Margins

The margins of the North Atlantic Ocean, including the Newfoundland and Iberian Margins, present two distinct episodes of rifting: at Permian–Trias times and in the middle Cretaceous. In the South Atlantic Ocean, rifting occurred on the location of the Pan-African suture, more than 450 Ma after its formation, and the two events are clearly dissociated. At first order, the geodynamic segmentation of the South and Equatorial Atlantic Oceans leads to the formation of different types of passive margins, showing a relationship between the regional geodynamic context and the structural architecture of passive margins. The Central Segment of the South Atlantic Ocean is characterized by sedimentary basins with pre- and syn-break-up magmatism, and the presence of an approximately 1–2 km-thick salt layer in the so-called continent-ocean transition, overlying a mainly non-marine sequence

Etude géologique et géophysique des marges continentales passives (Exemple du Zaïre et de l'Angola)

Ce travail aborde la formation des marges continentales passives dans le segment central de l'océan Atlantique Sud, en intégrant une étude structurale et cinématique. L'étude structurale de la marge angolaise a été réalisée à partir de données de sismique réflexion et réfraction (campagne Zaïango). L'interprétation de ces données a permis d'individualiser la structure de la marge en trois domaines : continental, transitionnel et océanique et de déterminer quelque points majeurs sur sa structuration. La compréhension de la genèse d'une marge ne peut être approchée sans son homologue. Cette simple constatation montre toute l'importance que l'on doit apporter à la reconstruction cinématique initiale des continents et à ses contraintes imposées sur les mouvements horizontaux des plaques lithosphériques. Afin d'étudier la position des marges au moment de cette fermeture, c'est à dire avant l'amincissement, une étude globale intégrant l'ensemble des données disponibles, géophysiques et géologiques, océaniques et continentales, a été réalisée dans l'océan Atlantique Equatoriale et Sud. Le rôle de la déformation intraplaque africaine a été l'objet d'un attention poussée. Cette étude indique qu'il est impossible d'obtenir une fermeture plus serrée que celle qui conduit à la superposition des fronts salifères brésiliens et angolais : les coupes issues de la sismique réflexion des deux marges indiquent qu'il subsiste un bassin aminci, large de plus de 330 km et dont la croûte n'excède jamais 13 kilomètres d'épaisseur. L'étude cinématique et la description de l'évolution de la marge à partir des données sismiques montre donc que l'on ne peut envisager l'application d'un modèle de genèse des marges avec conservation de volume (type McKenzie ou Wernicke) : pour expliquer l'amincissement du bassin , il faudrait probablement nous intéresser aux modèles non-conservatifs qui sont déjà invoqués pour la formation des bassins continentaux, sans mouvements horizontaux.The objective of the present work is to study the formation of the passive continental margins of the Central Segment of the South Atlantic. We proposed a combined approach , which integrates structural constraints based on geological cross-sections and global constraints based on plate kinematic reconstructions. The structural study is based on MCS and refraction data collected during the Zaiango programme. Based on theses data, three structural domains (continental, transitional and oceanic) and their major characteristics have been defined. Understanding the formation of a margin cannot be approached without studying the homolog margin. Therefore, it is of major importance to reconstruct the initial fit and take into account the constraints imposed by the kinematic reconstructions on the lateral motions of the lithospheric plates. In order to assess the relative position of the plates at the ocean closure (prior to crustal thinning), a global study was thus performed, integrating all geophysical and geological constraints, in the ocean and on land, in South and Equatorial Atlantic Ocean. The role of african intra-plate deformation have been thoroughly studied. The kinematic best fitting poles show that it is impossible to close the margins beyond the superposition of the salt fronts, from the Angola and Brazil margins. The geological cross-sections based on seismic data from the homolog margins indicate that a 330 km wide basin with thin (<13 km) crust was present at the time of the fit) the evolution described shows that we can not apply conservative models for margin formation (such as McKenzie and Wernicke). In order to explain this thinning, one should investigate non-conservative models such as those proposed in marginal or continental basins with no horizontal movments.BREST-BU Droit-Sciences-Sports (290192103) / SudocPLOUZANE-Bibl.La Pérouse (290195209) / SudocSudocFranceF

TRAIL et choc thermique (synergie d'induction de l'apoptose des cellules leucémiques)

Cette étude montre que la combinaison de traitement par TRAIL (TNF-Related Apoptosis Inducing Ligand) et choc thermique stimule fortement l'apoptose de cellules leucémiques, dont celles de patients atteints de LLC. De plus, ce co-traitement n'est pas toxique pour des lymphocytes normaux, ouvrant donc de nouvelles perspectives dans la recherche d'alternatives aux traitements anti-cancéreux classiques. La stimulation d'apoptose observée dépend de l'activation des caspases, de la formation du DISC mais non d'une néo-synthèse protéique. Elle résulte d'une meilleure fixation de TRAIL aux récepteurs DR4 et DR5 à la surface cellulaire. De plus, les alcools, qui comme le choc thermique fluidifient les membranes, stimulent aussi l'apoptose induite par TRAIL. Ces synergies sont corrélées à une forte production de céramides, totalement inhibée par la drogue D609. La fluidité membranaire et les céramides sont donc 2 paramètres importants lors de la stimulation de l'apoptose induite par TRAIL lors de différents type de stressThis study reveals that TRAIL (TNF-Related Apoptosis Inducing Ligand) and heat shock combined treatment strongly stimulates apoptosis of leukaemia cells including cells from CLL patients. Moreover, this co-treatment is not toxic for normal T-lymphocytes, thus opening new prospects in search for alternatives to traditional anti-cancer therapies. The apoptosis stimulation is caspase- and DISC formation-dependent, but protein neo-synthesis-independent. The phenomenon is correlated with an enhanced recognition of TRAIL death receptors DR4 and DR5 by this cytokine. Moreover, alcohol, which like heat shock induces membranes fluidity, also enhances TRAIL-mediated apoptosis. These synergies correlate with drastic ceramide production, a phenomenon that is completely inhibited by the D609 drug. Membrane fluidity and ceramide are therfore two key parameters of the mechanism involved in stress-induced stimulation of TRAIL apoptosisLYON1-BU.Sciences (692662101) / SudocSudocFranceF