Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis

Background Cyclin-dependent protein kinase-5 (CDK5) is an unusual member of the CDK family as it is not cell cycle regulated. However many of its substrates have roles in cell growth and oncogenesis, raising the possibility that CDK5 modulation could have therapeutic benefit. In order to establish whether changes in CDK5 activity are associated with oncogenesis one could quantify phosphorylation of CDK5 targets in disease tissue in comparison to appropriate controls. However the identity of physiological and pathophysiological CDK5 substrates remains the subject of debate, making the choice of CDK5 activity biomarkers difficult. Methods Here we use in vitro and in cell phosphorylation assays to identify novel features of CDK5 target sequence determinants that confer enhanced CDK5 selectivity, providing means to select substrate biomarkers of CDK5 activity with more confidence. We then characterize tools for the best CDK5 substrate we identified to monitor its phosphorylation in human tissue and use these to interrogate human tumour arrays. Results The close proximity of Arg/Lys amino acids and a proline two residues N-terminal to the phosphorylated residue both improve recognition of the substrate by CDK5. In contrast the presence of a proline two residues C-terminal to the target residue dramatically reduces phosphorylation rate. Serine-522 of Collapsin Response Mediator-2 (CRMP2) is a validated CDK5 substrate with many of these structural criteria. We generate and characterise phosphospecific antibodies to Ser522 and show that phosphorylation appears in human tumours (lung, breast, and lymphoma) in stark contrast to surrounding non-neoplastic tissue. In lung cancer the anti-phospho-Ser522 signal is positive in squamous cell carcinoma more frequently than adenocarcinoma. Finally we demonstrate that it is a specific and unusual splice variant of CRMP2 (CRMP2A) that is phosphorylated in tumour cells. Conclusions For the first time this data associates altered CDK5 substrate phosphorylation with oncogenesis in some but not all tumour types, implicating altered CDK5 activity in aspects of pathogenesis. These data identify a novel oncogenic mechanism where CDK5 activation induces CRMP2A phosphorylation in the nuclei of tumour cells

Étude métallurgique d’armes de l’Âge du Fer en Franche-Comté

La lame, de ter ou de bronze, d’une épée, engagée dans une poignée massive, demande pour déceler son mode de montage l’utilisation de méthodes diverses : radiographie, analyse de la composition, essais de dureté, examen micrographique. La radiographie La radiographie des objets en bronze est plus difficile que celle des objets en fer, et nécessite du matériel plus puissant. L’appareil que nous avons utilisé est un Baltospot GM 300 (directionnel panoramique, foyer 2,2 × 2,2 m/M, 300 KV) appart..

Recherches archéologiques dans les Monts de Blond (Haute-Vienne). Apports chronologiques-Notes préliminaires.

International audienc

Guidelines for social life cycle assessment of products and organizations

info:eu-repo/semantics/publishe

Les âges du fer dans la vallée de la Saône (VIIe - Ier siècles avant notre ère)

La vallée de la Saône et ses environs se distinguent par leur richesse archéologique pour les deux Ages du fer et pour les vestiges relevant de la métallurgie ancienne. La comparaison des vestiges textiles, tombes à épées et tous les aspects de la paléométallurgie du bronze : mines, minerais, techniques de fabrication apporte des précisions sur cette période

CCL22 regulates experimental autoimmune encephalomyelitis by controlling inflammatory macrophage accumulation and effector function

CCL22 functions to regulate EAE development through CNS macrophage chemoattraction and the balance of macrophage inflammatory and anti-inflammatory cytokine expression

Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglan-dins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(−/−), COX-2(−/−), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(−/−) and increased in COX-2(−/−) mice, compared with their respective WT controls. This influx of leukocytes was accompanied by a marked disruption of blood–brain barrier and differential expression of chemokines. These results indicate that COX-1 and COX-2 deletion differentially modulate leukocyte recruitment during neuroinflammation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition is detrimental, during a primary neuroinflammatory response