Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

International audienc

How ubiquitination regulates the TGF-β signalling pathway: New insights and new players

Ubiquitination of protein species in regulating signal transduction pathways is universally accepted as of fundamental importance for normal development, and defects in this process have been implicated in the progression of many human diseases. One pathway that has received much attention in this context is transforming growth factor-beta (TGF-ß) signalling, particularly during the regulation of epithelial-mesenchymal transition (EMT) and tumour progression. While E3-ubiquitin ligases offer themselves as potential therapeutic targets, much remains to be unveiled regarding mechanisms that culminate in their regulation. With this in mind, the focus of this review highlights the regulation of the ubiquitination pathway and the significance of a recently described group of NEDD4 E3-ubiquitin ligase isoforms in the context of TGF-ß pathway regulation. Moreover, we now broaden these observations to incorporate a growing number of protein isoforms within the ubiquitin ligase superfamily as a whole, and discuss their relevance in defining a new ‘iso-ubiquitinome’

SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy

Mitochondrial Associated Ubiquitin Fold Modifier-1 Mediated Protein Conjugation in Leishmania donovani

In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis

Key role for ubiquitin protein modification in TGFβ signal transduction

The transforming growth factor β (TGFβ) superfamily of signal transduction molecules plays crucial roles in the regulation of cell behavior. TGFβ regulates gene transcription through Smad proteins and signals via non-Smad pathways. The TGFβ pathway is strictly regulated, and perturbations lead to tumorigenesis. Several pathway components are known to be targeted for proteasomal degradation via ubiquitination by E3 ligases. Smurfs are well known negative regulators of TGFβ, which function as E3 ligases recruited by adaptors such as I-Smads. TGFβ signaling can also be enhanced by E3 ligases, such as Arkadia, that target repressors for degradation. It is becoming clear that E3 ligases often target multiple pathways, thereby acting as mediators of signaling cross-talk. Regulation via ubiquitination involves a complex network of E3 ligases, adaptor proteins, and deubiquitinating enzymes (DUBs), the last-mentioned acting by removing ubiquitin from its targets. Interestingly, also non-degradative ubiquitin modifications are known to play important roles in TGFβ signaling. Ubiquitin modifications thus play a key role in TGFβ signal transduction, and in this review we provide an overview of known players, focusing on recent advances

Clinical performance of the Locator® attachements : a retrospective study with 1-8 years of follow-up

Le manuscrit ci-annexé vous présente les résultats de notre étude rétrospective qui évalue la performance clinique de l’attachement Locator®, partie connectique utilisé dans les cadre de prothèses dentaires partielles ou complètes amovibles implanto-portées. Le sujet de l’étude est d’intérêt puisque cet attachement est très fréquemment utilisé par les médecin-dentistes, pour lesquels la maintenance post-insertion nécessite un suivi constant. Comme tous les types d’attachements disponibles sur le marché, ce système présente des faiblesses techniques. L’étude a consisté à suivre l’historique médico-dentaire de patients porteurs de l’attachement Locator® en rapportant les complications mécaniques inhérentes à cet attachement, et en évaluant son usure en fonction de multiples variables pouvant les influencer. Les conclusions dressées doivent permettre aux cliniciens d’anticiper le suivi adéquat lors de l’utilisation de ce système. Les résultats sont également en concordance avec les récentes améliorations de l’attachement apportées en 2017

La scolarisation des élèves allophones au collège : étude comparative des modalités d'organisation de quatre dispositifs d'accueil et des effets potentiels sur l'apprentissage du français

International audienceThis article presents a comparative study of four approaches to integrating migrant pupils into the French high school system.We examined the elements that facilitate the success of allophone pupils, including how the way they are integrated affects their ability to they learn. We shall analyze how they work in practice from two different standpoints: the intrinsic interest of each policy and how they transfer to the context of an “ordinary class."This qualitative research which consists of semi-directive interviews, point to the conclusion that the only real personalized approach for migrant learners lies in the specific integration policies, regardless of their structure.Cet article présente une étude comparative entre quatre dispositifs de scolarisation des élèves allophones au collège en France.Notre problématique consiste à interroger les éléments facilitateurs de la réussite des élèves allophones parmi lesquels figure la question des modalités d’accueil et de leurs effets sur les apprentissages des élèves. Nous analyserons leur prise en charge au sein des dispositifs cibles à partir de deux focales: l’intérêt intrinsèque de chacun des dispositifs et leur articulation avec «&nbsp;la classe ordinaire&nbsp;».Les conclusions de cette recherche qualitative qui consiste en des entretiens semi-directifs menés auprès d’élèves allophones et d’enseignants tendent à soutenir que le seul véritable parcours personnalisé et adapté aux apprenants allophones s’inscrit dans les dispositifs d’accueil spécifiques qui leur sont réservés qu’elle qu’ait été leur structure.</p

L'apprentissage-acquisition du FLE/S par les élèves allophones : la construction de l'interlangue de l'apprenant

International audienceNotre recherche porte sur les élèves allophones au collège. Dans ce contexte, le français a un statut de langue de socialisation mais aussi de langue de scolarisation (Verdelhan-Bourgade, 2002). L’acquisition de la langue seconde est un impératif pour ces adolescents car elle conditionnera la réussite de leur scolarité. Or, les constats quant à la réussite des élèves allophones au collège sont plutôt alarmants. Nos observations empiriques ont notamment montré qu’à la fin de la 3ème, la plupart d’entre eux échouaient au Brevet des collèges et étaient massivement orientés par défaut et en raison d’une maîtrise insuffisante de la langue en filière professionnelle. Ces constats avaient été formalisés dans l’enquête Pisa de 2008, commandée par la Commission européenne. Celle-ci avait notamment souligné au sein des principaux pays européens dont la France « la surreprésentation des élèves immigrants dans l’enseignement professionnel » et leur quasi absence dans l’enseignement supérieur. Nous présenterons, au cours de cet article, plusieurs pistes qui pourraient permettre l’amélioration de l’apprentissage/acquisition du FLE/S par ces élèves allophones débutants en collège et ce, en lien constant avec les modalités de leur prise en charge au sein des collège

Récits d'expériences d'élèves allophones en classe ordinaire au collège : entre intériorisation douloureuse de la norme scolaire et rejet de son identité

International audienceOur research concerns modes of educating allophone pupils in middle school. We try to understand the reasons behind the academic failure of many of these pupils within the French school system. This failure is revealed in two ways at the middle school level: the majority of allophone pupils do not obtain the French General Certificate of Secondary Education and they are almost systematically oriented towards vocational fields (European Commission, 2008). These reports were confirmed during our previous research (Guedat-Bittighoffer and Dat 2009, 2012). Our article analyzes the discourse of some of these pupils collected in 4 welcoming classes during semi-directive interviews. We shall show in particular that the allophone pupils interiorized "the normative consciousness" (Dabène 1994) of the institution as regards their language skills and that they are very often subject to negative perceptions of their multilingualism