La restitución como objetivo y el problema de los leonesismos en los Spanish Grail Fragments editados por Karl Pietsch

Integran este número de la revista ponencias presentadas en Studia Hispanica Medievalia VIII: Actas de las IX Jornadas Internacionales de Literatura Española Medieval, 2008, y de Homenaje al Quinto Centenario de Amadis de Gaula

The Neurofibromatosis 2 tumor suppressor merlin in cytoskeleton organization and cell cycle regulation

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder, which predisposes to multiple tumours of the nervous system, typically schwannomas and meningiomas. Biallelic inactivation of the NF2 gene occurs both in sporadic and NF2-related schwannomas and in most meningiomas. The NF2 gene product merlin (or schwannomin) is structurally related to the ERM proteins, ezrin, radixin and moesin, which act as molecular linkers between the actin cytoskeleton and the plasma membrane. Merlin is a tumor suppressor that participates in cell cycle regulation. Merlin s phosphorylation status appears to be associated with its tumour suppressor activity, i.e. non-phosphorylated merlin functions as a tumour suppressor, whereas protein phosphorylation results in loss of functional activity. This thesis study was initiated to investigate merlin s role as a tumor suppressor and growth inhibitor. These studies show, that like many other tumor suppressors, also merlin is targeted to the nucleus at some stages of the cell cycle. Merlin s nuclear localization is regulated by cell cycle phase, contact inhibition and adhesion. In addition, a potential nuclear binding partner for merlin was identified, Human Enhancer of Invasion 10 (HEI10), a cyclin B interacting protein. Many tumor suppressors interact with microtubules and this thesis work shows that also merlin colocalizes with microtubules in mitotic structures. Merlin binds microtubules directly, and increases their polymerization in vitro and in vivo. In addition, primary mouse Schwann cells lacking merlin displays disturbed microtubule cytoskeleton. Fourth part of this thesis work began from the notion that PKA phosphorylates an unidentified site from the merlin N-terminus. Our studies show that serine 10 is a target for PKA and modulation of this residue regulates cytoskeletal organization, lamellipodia formation and cell migration. In summary, this thesis work shows that merlin s role is much more versatile than previously thought. It has a yet unidentified role in the nucleus and it participates in the regulation of both microtubules and the actin cytoskeleton. These studies have led to a better understanding of this enigmatic tumor suppressor, which eventually will aid in the design of specific drugs for the NF2 disease.

Functional regulation of the Neurofibromatosis 2 tumor suppressor merlin

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder manifested by the formation of multiple benign tumors of the nervous system. Affected individuals typically develop bilateral vestibular schwannomas which lead to deafness and balance disorders. The syndrome is caused by inactivation of the NF2 tumor suppressor gene, and mutation or loss of the NF2 product, merlin, is sufficient for tumorigenesis in both hereditary and sporadic NF2-associated tumors. Merlin belongs to the band 4.1 superfamily of cytoskeletal proteins, which also contain the related ezrin, radixin, and moesin (ERM) proteins. The ERM members provide a link between the cell cytoskeleton and membrane by connecting membrane-associated proteins to actin filaments. By stabilizing complexes in the cell cortex, the ERMs modulate morphology, growth, and migration of cells. Despite their structural homology, overlapping subcellular distribution, direct molecular association, and partial overlap of molecular interactions, merlin and ezrin exert opposite effects on cell proliferation. Merlin suppresses cell proliferation, whereas ezrin expression is linked to oncogenic activity. We hypothesized that the regions which differ between the proteins might explain merlin s specificity as a tumor suppressor. We therefore analyzed the regions, which are most diverse between merlin and ezrin; the N-terminal tail and the C-terminus. To determine the properties of the C-terminal region, we studied the two most predominant merlin isoforms together with truncation variants similar to those found in patients. We also focused on the evolutionally conserved C-terminal residues, E545-E547, that harbor disease causing mutations in its corresponding DNA sequence. In addition to inhibiting cell proliferation, merlin regulates cytoskeletal organization. The morphogenic properties of merlin may play a role in tumor suppression, since patient-derived tumor cells demonstrate cytoskeletal abnormalities. We analyzed the mechanisms of merlin-induced extension formation and determined that the C-terminal region of amino acids 538-568 is particularly important for the morphogenic activity. We also characterized the role of C-terminal merlin residues in the regulation of proliferation, phosphorylation, and intramolecular associations. In contrast to previous reports, we demonstrated that both merlin isoforms are able to suppress cell proliferation, whereas C-terminally mutated merlin constructs showed reduced growth inhibition. Phosphorylation serves as a mechanism to regulate the tumor suppressive activity of merlin. The C-terminal serine 518 is phosphorylated in response to both p21-activated kinase (PAK) and protein kinase A (PKA), which inactivates the growth inhibitory function of merlin. However, at least three differentially phosphorylated forms of the protein exist. In this study we demonstrated that also the N-terminus of merlin is phosphorylated by AGC kinases, and that both PKA and Akt phosphorylate merlin at serine 10 (S10). We evaluated the impact of this N-terminal tail phosphorylation, and showed that the phosphorylation state of S10 is an important regulator of merlin s ability to modulate cytoskeletal organization but also regulates the stability of the protein. In summary, this study describes the functional effect of merlin specific regions. We demonstrate that both S10 in the N-terminal tail and residues E545-E547 in the C-terminus are essential for merlin activity and function.

Campanha de comunicação de Ambient Media para a marca Leroy Merlin

Trabalho de projeto apresentado à Escola Superior de Comunicação Social como parte dos requisitos para obtenção de grau de mestre em Publicidade e Marketing.

« Recherches de plusieurs singularités, par Françoys MERLIN, controlleur général de la maison de feu madame Marie-Élizabeth, fille unique de feu roy Charles dernier,... portraictes et escrites par Jacques Cellier, demourant à Reims. » (4583-1587).

Recueil de dessins à la plume, modèles d'écriture, d'architecture ; Oraison dominicale et alphabets en plusieurs langues ; dessins de l'église cathédrale et de Saint-Rémy de Reims, de Notre-Dame de Paris, et autres monuments parisiens ; dessins d'instruments géographiques et astronomiques, d'instruments de musique, etc. ; — (fol. 193) « Ensuivent plusieurs portraicts tracés en escriture. »

« Recherches de plusieurs singularités, par Françoys MERLIN, controlleur général de la maison de feu madame Marie-Élizabeth, fille unique de feu roy Charles dernier,... portraictes et escrites par Jacques Cellier, demourant à Reims. » (4583-1587).

Recueil de dessins à la plume, modèles d'écriture, d'architecture ; Oraison dominicale et alphabets en plusieurs langues ; dessins de l'église cathédrale et de Saint-Rémy de Reims, de Notre-Dame de Paris, et autres monuments parisiens ; dessins d'instruments géographiques et astronomiques, d'instruments de musique, etc. ; — (fol. 193) « Ensuivent plusieurs portraicts tracés en escriture. »

Catalogue d'une collection très importante de planches gravées en tous genres par les maîtres et artsites les plus célèbres du XVe au XIXe siècle, formant la 1re partie du fonds de commerce d'éditeur d'estampes de Mme veuve Auguste Jean, dont la vente, par cessation définitive de commerce, aura lieu... les lundi 2, mardi 3, mercredi 4 et jeudi 5 février 1846... Hôtel de ventes mobilières, place de la Bourse, 2... / Me Merlin, commissaire-priseur ; M. Vallée, expert, rue de Chartres-Saint-Honoré, n° 8...

[Vente. Art. 1846-02-02 - 1846-02-05. Paris]

Catalogue des planches gravées en tous genres par les plus célèbres graveurs du XVe au XIXe siècle, composant le fonds de commerce d'éditeur d'estampes de Mme Vve Auguste Jean. Deuxième partie dont la vente, par continuation et par suite de cessation de commerce, aura lieu les mardi 16, mercredi 17, jeudi 18 et vendredi 19 juin 1846 et le lundi suivant, 22 juin, pour les cartes géographiques... Hôtel de ventes mobilières, place de la Bourse, n° 2... / Me Merlin, commissaire-priseur ; M. J. Vallée, expert, rue de Chartres-Dt.-Honoré, 8

[Vente. Art. 1846-06-16 - 1846-06-22. Paris]

Catalogue des planches gravées en tous genres par les plus célèbres graveurs du XVe au XIXe siècle, composant le fonds de commerce d'éditeur d'estampes de Mme Vve Auguste Jean. Troisième partie dont la vente, par continuation et par suite de cessation de commerce, aura lieu les mardi 24, mercredi 25, jeudi 26, vendredi 27 et samedi 28 novembre 1846... Hôtel de ventes mobilières, place de la Bourse, n° 2... / Me Merlin, commissaire-priseur ; M. J. Vallée, expert, rue de Chartres-Dt.-Honoré, 8

[Vente (Art). 1846-11-24 - 1846-11-28. Paris]

Histoire du Saint-Graal, et Histoire de Merlin, par ROBERT DE BORON.

Contient : Histoire du Saint-Graal, par ROBERT DE BORON. « [C]hil ki se tient et juge au plus peceor de tous, mande salus... » [Le Saint Graal, éd. Hucher, II, 3, note] ; « ... et commenche messire ROBERS en tel manière [Ibid., III, 303], comme vos poerés oïr, s'il est ki le vos die. Or nous consaut Sainte Marie. Explicit li commencemens de l'estoire del s. Graal, et chi après vient l'estoire de Merlin. Dieu nous maint tous à boine fin. Amen. » [Cf. l'explicit dans le ms. franç. 95] ; Histoire de Merlin, par ROBERT DE BORON. « Mout fut iriés li anemis, quant nostre sires ot estei en enfer... » ; «... si come li contes le vous devisera cha avant. Explicit l'enserrement de Merlin. Diex nous maint tous à boine fin. Amen »

« La memorable Hystoire de Merlin » [de ROBERT DE BORRON].

Commençant par : « Moult furent corrociez les ennemis... » et finissant par : «... il perdit le chastel de Trebes, si comme le compte le vous devisera puis apres. Et cy finist l'Ystoire de Merlin. Explicit » .

« La Prophecie MERLIN ».

Commençant par : « Touz pecheurs doibvent sçavoir que davant que Nostre Seigneur vensist en terre... » et finissant par : «... Ainsi fut Artus esleu à roy, et tint la terre et le royaume de Longres longtemps en paiz. G. Papin. « Icy finist la prophecie Merlin, Redigée de picart en franczoys Qui est tel quel, au mieulx que l'entendoys ; A l'escripvain doint Jhesus bonne fin » .