Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

Optimisation des étapes de croissance épitaxiale pour la réalisation de systèmes intégrés sur silicium

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Une allée sépulcrale de la fin du Néolithique : « le Cimetière aux Anglais » à Vauréal (Val-d’Oise), relecture des données, 2014-2015

National audienceà veni

Extraction, purification and chemical characterisation of xylogalacturonans from pea hulls

International audienc

Genetic Alterations and Oncogenic Pathways in Hepatocellular Carcinoma

International audienceA bstract : Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. Chronic infections with the hepatitis B virus (HBV) and the hepatitis C virus (HCV) have been implicated in about 80% of cases worldwide, and other known environmental risk factors, including alcohol abuse and dietary intake of aflatoxin B1, might synergize with viral infections. Recent insight into the molecular mechanisms leading to HCC development has been provided by the identification of major genetic abnormalities revealed by genomewide allelotype studies and molecular cytogenetic analysis. Moreover, several oncogenic pathways have been implicated in malignant transformation of liver cells. Inactivation of the p53 tumor suppressor gene by mutations and allelic deletions in about 30% of HCC cases has been associated predominantly with exposure to aflatoxin B1 and HBV infection. By contrast, a mutation in the β‐catenin gene in around 22% of HCCs is more rare in HBV‐associated tumors. Activation of cyclin D1 and disruption of the Rb pathway are also commonly involved in liver tumorigenesis. New major challenges include the identification of candidate genes located in frequently altered chromosomal regions and that of oncogenic pathways driven by different risk factors. This search might shed some light on the tumorigenic role of HBV and HCV. It might also permit accurate evaluation of major targets for prognostic and therapeutic intervention

Interaction and Functional Cooperation between the LIM Protein FHL2, CBP/p300, and β-Catenin

Transcriptional activation of gene expression by Wnt signaling is driven by the association of β-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate β-catenin transactivating activity and that β-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced β-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and β-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and β-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2(−/−) embryo fibroblasts, the transactivation activity of β-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the β-catenin/TCF complex in FHL2(−/−) cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on β-catenin. Furthermore, we found that FHL2 significantly increased acetylation of β-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and β-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF

Acetylation of β-Catenin by p300 Regulates β-Catenin-Tcf4 Interaction

Lysine acetylation modulates the activities of nonhistone regulatory proteins and plays a critical role in the regulation of cellular gene transcription. In this study, we showed that the transcriptional coactivator p300 acetylated β-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of β-catenin for Tcf4, and the cellular Tcf4-bound pool of β-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by β-catenin/Tcf4 and that the cooperation between p300 and β-catenin was severely reduced by the K345R mutation, implying that acetylation of β-catenin plays a part in the coactivation of β-catenin by p300. Interestingly, acetylation of β-catenin had opposite, negative effects on the binding of β-catenin to the androgen receptor. Our data suggest that acetylation of β-catenin in the arm 6 domain regulates β-catenin transcriptional activity by differentially modulating its affinity for Tcf4 and the androgen receptor. Thus, our results describe a new mechanism by which p300 might regulate β-catenin transcriptional activity

L’habitat Néolithique récent du Pré-à-Vaches à Morains-le-Petit (Val-des-Marais, Marne)

Le corpus d’objets du site du Pré-à-Vaches constitue un ensemble très conséquent et rare parce qu’il correspond à un habitat très probablement attribuable au tout début du Néolithique récent. Le contexte de découverte, la constitution de la collection, la datation et la caractérisation typologique, technologique et culturelle des différentes industries permettent de mieux situer cet assemblage au sein du Néolithique récent. Le site comprend plus de 800 objets et présente notamment un ensemble assez exceptionnel d’industrie en bois de cerf pour un site terrestre. Il apporte également de précieuses informations sur l’industrie lithique et céramique de cette période. Quelques éléments de parure ont également été trouvés dans cet habitat. Les études des différentes catégories d’objets ont permis une bonne caractérisation typologique et chronologique du site. Quelques éléments témoignent d’héritages du Néolithique moyen. Malgré le caractère ponctuel des fouilles et les lacunes concernant l’organisation spatiale des structures, des activités de débitage du bois de cerf et surtout de taille du silex ont été mises en évidence.The corpus from the Pré-à-Vaches site represent a large and rare collection, corresponding to a settlement that almost certainly dates to the very beginning of the Recent Neolithic. The article discusses the context of discovery, the making of the collection, as well as presenting dating and the typological, technological and cultural characteristics ofthe artefacts. The antler tool assemblage is quite exceptional for a dryland settlement. The flint industry and the pottery also provide interesting information for this period. There are also some ornaments from the settlement. Typological and chrono-cultural characterisation of the site have been realised by the different studies. Some elements represent héritages of the Middle Neolithic period. The spatial organisation of the dwelling site is unknown, but activities of deer-antler debitage and flint-knapping hâve been highlighted

L’habitat Néolithique récent du « Pré à Vaches » à Morains-le-Petit (Val-des-Marais, Marne)

International audienc