Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation

An understanding of the mechanisms determining MYC's transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.Peer reviewe

CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection

The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A ( CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2A(HOZ)) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2A(HOZ) mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4(+) T-cells and CD8(+) effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2A(HOZ) as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects.Peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Fonction des facteurs de transcription de la famille snail dans les cancers du sein et du côlon

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Changes in soluble carbohydrates, lipid peroxidation and antioxidant enzyme activities in the embryo during ageing in wheat grains

International audienceSoluble sugar contents and antioxidant enzyme activities were measured in the embryo of wheat (Triticum aestivum) seeds throughout the desiccation phase of maturation in 2003 and 2004 to investigate whether they were related to seed quality. Whatever the date of harvest after the end of filling, seeds tolerated artificial drying in the ears, and almost all of them germinated at 10 8C whereas they were dormant at 30 8C. Their sensitivity to 5 day accelerated ageing treatment (45 8C, 100% relative humidity) slightly decreased during desiccation. This phase of development was associated with an accumulation of sucrose and raffinose, and an increase in the raffinose/sucrose ratio in the embryo. Artificial drying in the ears resulted in an increase in both sugars, but especially raffinose, and in the maintenance of a high value (around 0.6–0.7) of the raffinose/sucrose ratio. Superoxide dismutase, catalase and glutathione reductase activities did not change markedly in the embryo after mass maturity. They were sufficiently active to maintain malondialdehyde and H 2 O 2 contents at very low levels. No clear relationship existed between the antioxidant enzyme activities and seed quality, whereas seed tolerance to ageing seemed to be related to a high value of the raffinose/sucrose ratio.

Ingestion de larves vivantes de mouches soldat noires (Hermetia illucens) par le poulet de chair

National audienc

La Belgique du XIXe siècle, carrefour stratégique de la clandestinité européenne ?

Des proscrits du Second Empire aux carlistes espagnols, des anarchistes de tous bords aux patriotes polonais et italiens, tous se sont retrouvés à un moment ou à un autre à mener leur combat depuis la Belgique. Dans une Europe encore largement sous la férule de monarques absolutistes et de gouvernements autoritaires, la Belgique du 19e siècle fait en effet figure d’exception. Sa constitution, élevée au rang de texte fondateur de la patrie, garantit tous les droits et libertés qui définissent encore aujourd’hui un état démocratique : séparation des trois pouvoirs, égalité des citoyens devant la loi, garantie des libertés fondamentales telles que les libertés de la presse, de culte, de réunion et d’association. L’impossibilité légale d’extrader les criminels politiques, la situation géographique du pays – à mi-chemin de Londres, Paris et Berlin et disposant d’une ouverture sur la mer – et ses nombreuses voies de communication contribuent également à faire de la Belgique le refuge idéal pour toutes les organisations clandestines en Europe. Mais comment ces groupes clandestins s’adaptent-ils aux possibilités nouvelles offertes par la Belgique, tant du point de vue organisationnel que dans leur rapport au pouvoir politique et à la société dans laquelle ils s’insèrent ? Conservent-ils les mêmes schémas organisationnels fractionnés et décentralisés, nécessaires dans le cadre de leur action clandestine, que dans leur pays d’origine, ou les abandonnent-ils au profit d’une organisation plus souple et plus efficace, mais aussi moins discrète ? Entretiennent-ils les mêmes sentiments de répulsion et de méfiance à l’égard des autorités du pays qui les accueille que par rapport à celui qu’ils combattent, ou se rangent-ils « dans le rang » afin de faciliter leurs démarches et la mise en place de leurs plans d’action ? La répartition géographique des différentes communautés d’étrangers établies en Belgique influence-t-elle le choix de leur implantation dans telle région spécifique plutôt qu’une autre ? Quels contacts, quels rapports entretiennent-ils, tant avec la population belge qu’avec leurs compatriotes établis librement en Belgique ? Des collaborations ont-elles pu se développer entre diverses organisations clandestines menant parallèlement leur combat depuis la Belgique ? Si le cas des proscrits du Second Empire est bien connu, notamment en ce qui concerne leur mainmise sur la plupart des grands journaux de la presse belge, véritables tribunes d’où ils ont pu continuer la lutte contre Napoléon III ; les formes de lutte et les moyens d’actions de tous ces groupes clandestins en Belgique n’ont en revanche été que rarement étudiés. Il nous faut également nous interroger sur le regard que portent les autorités belges sur ces groupes clandestins, alors même que les traités internationaux qui ont officialisé l’indépendance de la Belgique lui ont imposé la neutralité et interdit toute ingérence dans les affaires intérieures de ses voisins. Constamment tenues au courant des allées et venues des membres de ces différents groupes clandestins sur leur territoire par la police des étrangers, les autorités belges ont pourtant fait preuve d’un certain laxisme dès lors qu’il s’agissait de les combattre, même lorsque la constitution le rendait possible, ce qui mérite une attention toute particulière. Cette communication aura donc pour but de mener une première analyse sur les implications qu’a pu avoir pour ces groupes clandestins cet établissement en Belgique, tant sur leurs formes d’organisation que sur leur rapport à la société