Comptant parmi les figures les plus éminentes de la littérature arthurienne, célèbre au Moyen Âge comme dans les périodes postérieures, Merlin demeure pourtant un personnage polymorphe et contradictoire. Un double angle d’étude permettra de saisir ses ambiguïtés et de constituer une poétique du personnage. D’abord, dans une perspective relationnelle, le bestiaire, c’est-à-dire la faune littéraire, constitue un élément de sa définition. Dans les Suites rétrospectives du Merlin en prose (la Suite dite « Vulgate » la Suite dite « Post-Vulgate » et le Livre d’Artus), romans qui constituent l’aboutissement des proses arthuriennes du XIIIe siècle, cet axe relationnel rencontre ensuite une perspective intertextuelle. Par son extension et sa nature, le bestiaire merlinien se révèle extrêmement variable et difficilement classable, à l’image du personnage. Présidant aux relations entre le personnage et le bestiaire, les paradigmes de l’incarnation et de la voix, ainsi que la dialectique intus/foris, laissent percevoir une complexification croissante de Merlin, qui allie un rôle de vates responsable de la fiction et du bestiaire prophétique et une dimension proprement romanesque à l’issue du Merlin en prose. Enfin, dans les Suites du Merlin en prose, le bestiaire rend aussi bien compte du (re)développement et de la fin conjoints de ces deux aspects du personnage que de la poétique des textes. Par le biais de relations métonymiques, métaphoriques et analogiques avec Merlin, le bestiaire construit ainsi trois conceptions synchroniquement contrastées du personnage, en adéquation avec la tonalité et les objectifs poétiques différents des Suites. Il participe alors du message moral et des réflexions poétiques que chacun de ces romans, conscient de ses enjeux, véhicule. / One of the most eminent figures of Arthurian literature, renowned in the Middle Ages as in later periods, Merlin remains however a polymorphous and contradictory character. A study focusing on two aspects will allow us to perceive his ambiguities and to form the poetics of the character. Firstly, from a relational perspective, the bestiary, that is to say the literary fauna, constitutes an element of this definition. In Prose Merlin’s retrospective prose sequels (the “Vulgate” Suite, the “Post-Vulgate” Suite and the Livre d’Artus), romances which constitute the apex of thirteenth century Arthurian texts in prose, this relation axis encounters an intertextual perspective. By its extent and its nature the Merlin bestiary reveals itself to be extremely variable and difficult to categorize, as is the nature of the character. The paradigms of incarnation and voice, together with the intus/foris dialectics, that govern the relations between the character and the bestiary, show that Merlin becomes increasingly complex, because he combines a role of vates responsible for the fiction and the prophetic bestiary with a distinctly romantic dimension by the end of the Prose Merlin. Finally, in the Prose Merlin sequels, the bestiary also explains both the (re)development and the end of these two aspects of the character, as well as the poetics of the texts. Through the metonymical, metaphorical and analogical relations with Merlin, the bestiary thus builds up three different synchronically contrasting conceptions of the character, matching the tone and the various poetical purposes in the Suites. It contributes thus to the moral message and the poetical thoughts that each of these romances, aware of their portent, consciously carry.

The Neurofibromatosis 2 (NF2) disorder affects approximately l in 40,000 individuals. The primary physical manifestations of the disease are formation of bilateral vestibular schwannomas that lead to hearing and balance impairment (Evans et al 1992). Mutations in the ef2 gene, located on chromosome 22 in humans, have been mapped to all 17 exons. The nj2 gene encodes merlin, a 595 amino acid tumor suppressor protein that is believed to regulate mitogenic signaling in Schwann cells (SCs ). An in-frame deletion of exon 2 has been shown to lead to a more severe form of the disorder (Baser et al 2005). Exon 2 encodes amino acids 40-80 that serve as a paxillin binding domain l (PBD l) that is necessary for merlin's localization to the plasma membrane (Fernandez-Valle et al 2002). An nf2flox2/flxo2 mouse model was developed for conditional deletion of nj2 exon 2 using the Cre-Lox system (Giovannini 2000). These mice developed schwannomas by l 0 months of age. The goal of this thesis was to develop an in vitro model for studying the loss of merlin expression in SCs. SCs were removed from nf2flox2/flxo2 mice, and were infected in vitro with an adenovirus expressing Cre-Recombinase (Adeno-Cre) to excise exon 2, or with an adenovirus expressing B-Gal (Adeno-B-Gal) as a control. SCs were studied for nine days after infection. The nf2flox2/flxo2 SCs expressed nuclear CreRecombinase (Cre) by two days post-infection, and underwent a change in morphology beginning at day three. SCs transitioned from a typically bipolar shape when confluent to either a rounded and spread morphology or extended many processes becoming multipolar. Also by three days post-infection, there was a decrease in the expression of merlin, and a loss of its plasma membrane localization in ere-expressing SCs. Furthermore, there was a persistent increase in erbB2 expression at the plasma membrane in filopodia and other membrane protrusions in ere-expressing SCs. Finally, nf2flox2/flxo2 SCs expressing Cre displayed disordered growth by nine days post-infection in sub confluent cultures. These results suggest that Adeno-Cre viral infection of nf2flox2/flxo2 SCs in vitro leads to phenotypic changes observed in human schwannoma cells, and therefore is a suitable model for the study of loss of merlin expression in SCs.

No description available.

Yes / Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4(DCAF1). Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

Merlin is a tumour suppressor protein that is frequently mutated or downregulated in cancer. Biallelic Merlin inactivation is causative of tumour formation, including schwannoma, meningioma and ependymoma. These tumours can occur sporadically or as part of the genetic condition Neurofibromatosis type 2 (NF2) and cause significant morbidity. The current treatment options are restricted to surgery and radiotherapy, which are invasive and may cause further tumour development. The activity of both the E3 ubiquitin ligase complex Cullin 4 really interesting new gene (RING) E3 ubiquitin ligase- DNA damage binding protein (DDB1) and Cullin 4 associated factor 1 (CRL4-DCAF1) and Kinase suppressor of RAS 1 (KSR1) have been shown to be upregulated in schwannoma to drive tumour growth. KSR1 has also been shown to interact with components of the CRL4-DCAF1 complex. We investigated the expression, interaction and therapeutic potential of targeting these proteins in Merlin deficient schwannoma and meningioma using a primary human cell model and relevant cell lines. We found that DCAF1 and KSR1 protein were overexpressed in schwannoma and meningioma and confirmed that targeting both DCAF1 and KSR1 in meningioma had additive effects on proliferation. We also identified that CRL4-DCAF1 facilitates KSR1 dependent RAF/Mitogen-activated protein kinase (MAPK)/ Extracellular signal regulated kinase (ERK) kinase (MEK)/ERK pathway activity. We showed MLN3651, a neddylation inhibitor that targets ubiquitin ligase activity, reduced proliferation and activated apoptosis in Merlin-deficient tumours. We also showed that Merlin-positive tumours were less sensitive to MLN3651 than Merlin-deficient tumours; therefore, MLN3651 sensitivity may be CRL4-DCAF1-dependent. Finally, combination of MLN3651 and the MEK1/2 inhibitor AZD6244 had additive effects, particularly in meningioma. Combinatorial therapy activated the Hippo pathway, inhibited RAF/MEK/ERK pathway activity and proliferation demonstrating that targeting the activity and downstream pathways of both DCAF1 and KSR1 represents an attractive novel therapeutic strategy in Merlin-deficient tumours.

No description available.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thèse de doctorat : Lettres : Paris Est : 2008. Thèse de doctorat : Lettres : Université de Bâle, Suisse : 2008. / Titre provenant de l'écran-titre.

Le fragment de la Suite du Roman de Merlin que nous éditons est conservé dans quatre manuscrits (ms. de Londres, British Library, Additional 38117, le ms. Cambridge University Library, Additional 7071, le ms. de la Bibilothèque Nationale de France, fr. 112 - ms. de base de notre édition, et le ms. d'Imola, Biblioteca Comunale, ms. 135 AA25 n o 9 (7)). Par rapport aux trois éditions de la Suite déjà existantes (O. Sommer, Die Abenteuer Gawains Ywains und Le Morholts mit Den Drei Jungfrauen (Zeitschrift für Romanische Philologie, Beiheft 47, 1913), P. C. Smith (Les enchantemenz de Bretagne, Chapel Hill, 1977), édition réalisée à partir du ms. Cambridge, et G. Roussineau (La Suite du Roman de Merlin, Droz, 1996), édition effectuée essentiellement à partir du ms. de Londres), l'objectif de notre édition est de fournir un texte de la Suite du Roman de Merlin établi à partir du ms. BNF 112, selon les principes modernes d'édition des textes médiévaux, et comportant un apparat critique à deux niveaux. Nous avons essayé d'offrir un grand nombre de variantes détaillées, fournies par les autres témoins de l’œuvre, en limitant nos interventions à des corrections qui s'imposent. Le texte de l'édition est suivi par des notes explicatives, un glossaire et un index des noms propres. Sur le plan linguistique, nous avons relevé des traits qui rattachent notre ms. au domaine du Nord (conseilh ; karoloient, etc.), des tournures modernes par rapport aux autres témoins de l’œuvre et un certain nombre de termes (baudel ; pourvillier) qui peuvent enrichir la base du Dictionnaire du Moyen Français. / The fragment of the Suite du Roman de Merlin that we edited is preserved in four manuscripts (London manuscript, British Library, Additional 38117, the Cambridge University Library manuscript, Additional 7071, the BNF 112 manuscript, which is the main manuscript of our edition, and the Imola manuscript, Biblioteca Comunale, ms. 135 AA25 n° 9 (7)). Comparing to the other three already existing editions of the Suite (O. Sommer, Die Abenteuer Gawains Ywains und Le Morholts mit Den Drei Jungfrauen (Zeitschrift für Romanische Philologie, Beiheft 47, 1913), P. C. Smith (Les enchantemenz de Bretagne, Chapel Hill, 1977), edition based upon the Cambridge manuscript, and G. Roussineau (La Suite du Roman de Merlin, Droz, 1996), edition mainly based upon the London manuscript), the aim of our edition is to offer a text of the Suite du Roman de Merlin based upon the BNF 112 manuscript, according to the modern principles applied in the transcription of the medieval texts. We offered a great number of variants given by the other manuscritpts of the Suite and limited our interference with the text only for corrections which we considered strictly necessary. The text of our edition is followed by notes, a glossary and an index of names. On the linguistic level, we noted regional caracteristics that lead us to consider that our manuscript belongs to the North domain (conseilh ; karoloient, etc.), modern structures comparing to the other manuscripts of the Suite and a certain number of termes (baudel ; pourvillier) which can improve the DMF (Dictionnaire du Moyen Français) basis.

Neurofibromatosis type 2 is an autosomal dominant disease characterized by the formation of schwannomas and other peripheral neuropathies. The nf2 gene encodes the protein Schwannomin, or merlin. Schwannomin (Sch) is a membrane-cytoskeletal linking protein that suppresses cell proliferation at high cell density and modulates cell shape. Sch's tumor suppressive activity is regulated by its localization, conformation, and phosphorylation at serine 518 (S518). Sch's localization is dependent on binding the scaffold protein, paxillin. Phosphorylation of Sch at S518 regulates its conformation and tumor suppressor function. In a negative feedback loop, unphosphorylated Sch restricts cell proliferation downstream of Rac and p21-activated kinase (Pak), whereas Pak-induced phosphorylation inactivates Sch's ability to inhibit Pak and cell proliferation. Little is known about the function of the phosphorylated form of Sch, or the molecular mechanisms leading to its phosphorylation. Here we demonstrate that Sch-S518 phosphorylation is dependent on paxillin-binding and plasma membrane localization in SCs. Phosphorylation of Sch at the plasma membrane is mediated by Cdc42-Pak and results in altered SC morphology and polarity. Moreover, we have identified two extracellular stimuli that trigger Sch-S518 phosphorylation; these are neuregulin (NRG) and laminin, two potent activators of SC proliferation and myelination. NRG promotes Sch-S518 phosphorylation downstream of ErbB2/ErbB3 through PKA, whereas laminin-1 stimulation of β1 integrin promotes Pak- dependent phosphorylation of Sch-S518. Additionally, we find that Sch promotes process formation and elongation in primary and myelinating SCs, independent of Sch S518 phosphorylation. However, Sch phosphorylation was found to influence SC differentiation, as expression of an unphosphorylatable variant, Sch-S518A, facilitated SC myelination, whereas expression of a phospho-mimicking variant, Sch-S518D, reduced the SC's ability to myelinate. Together, these findings have identified receptor-mediated and paxillin-dependent pathways that regulate phosphorylation and inactivation of Sch's tumor suppressor function. Additionally, these results have elucidated novel normal functions for Sch during peripheral nerve development and myelination, and identify novel therapeutic targets for treatment of NF2 and other peripheral neuropathies.