Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo

« Le français est une langue difficile ».

International audienc

« Le français est une langue difficile ».

International audienc

Le CER: instrument de planification des enseignements et d’évaluation des apprenants

International audienceInwieweit der Gemeinsame Europäische Referenzrahmen (GER) zur Unterrichtsplanung und ganz besonders zur Leistungsbewertung benutzt werden kann, untersuchen die beiden Autoren am Beispiel der DELF- und DALF- Diplome, die ab November 2007 in die Beurteilung von Französisch als Fremdsprache an den Schweizer Schulen (Ende Sek I) integriert werden sollen. Dazu müssen die Bewertungskriterien in den verschiedenen Testbereichen nicht nur transparent und vergleichbar sein und auf jedem Niveau bestimmten qualifikativen Aspekten der gesprochenen bzw. der geschriebenen Sprache genügen, sondern auch eine in Zeit und Aufwand angemessene Durchführung der Prüfungen gewährleisten.Im Beitrag von Riba und Luscher wird vor allem die Rolle vorausgehender Studien und Probetests, soliden Prüfertrainings, nachfolgender Vergleichskontrollen und eventueller Korrekturmassnahmen innerhalb der Prüfungszentren deutlich. Sie verweisen aber auch auf die Anbindung von Prüfungsaufgaben an das “normale” Unterrichtsgeschehen und schliesslich auf die Grenzen messbarer Leistungen: So lässt sich z.B. die interkulturelle Dimension nur schwer in festen Kriterien fassen und bewerten, was sich auch in dem unterschiedlichen Stellenwert ausdrückt, der Prüfungen in verschiedenen Kulturen zukommt. Am Ende bekennen sich die Autoren zu ihrem Credo, dass Sprachtests die Autonomie der Lerner fördern und deshalb so gerecht und zuverlässig wie möglich sein müssen. (Red.)Après la publication du cadre européen commun de référence pour les langues, le Centre international d'études pédagogiques de Sèvres a procédé à la réforme des certifications en français langue étrangère, le DELF et le DALF. Dans cet article, le responsable du bureau du DELF et du DALF au CIEP, et le responsable de ces certifications en Suisse analysent l'impact que le Cadre européen a ou peut avoir sur la planification des enseignements/apprentissages en français langue étrangère

Centres de langues universitaires : des salles multimédias aux espaces multifonctions, Table ronde.

International audienc

Centres de langues universitaires : des salles multimédias aux espaces multifonctions, Table ronde.

International audienc

Noninvasive prenatal diagnosis of Mendelian disorders for consanguineous couples by relative genotype dosage

Noninvasive prenatal diagnosis relies on the presence in maternal blood of circulating cell-free fetal DNA released by apoptotic trophoblast cells. Widely used for aneuploidy screening, it can also be applied to monogenic diseases (NIPD-M) in case of known parental mutations. Due to the confounding effect of maternal DNA, detection of maternal or biparental mutations requires relative haplotype dosage (RHDO), a method relying on the presence of SNPs that are heterozygous in one parent and homozygous in the other. Unavoidably, there is a risk of test failure by lack of such informative SNPs, an event particularly likely for consanguineous couples who often share common haplotypes in regions of identity-by-descent. Here we present a novel approach, relative genotype dosage (RGDO) that bypasses this predicament by directly assessing fetal genotype with SNPs that are heterozygous in both parents (frequent in regions of identity-by-descent). We show that RGDO is as sensitive as RHDO and that it performs well over a large range of fetal fractions and DNA amounts, thereby opening NIPD-M to most consanguineous couples. We also report examples of couples, consanguineous or not, where combining RGDO and RHDO allowed a diagnosis that would not have been possible with only one approach