Biomedical subjects

Marie Annick Buendia

Publications and source records attributed to Marie Annick Buendia.

10 recordsLinked to original sources

PubMed2006

The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.

The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation.

CREB-Binding Protein↗

PubMed2005

HBV induced carcinogenesis.

Hepatocellular carcinoma (HCC) is one of the rare human neoplasms associated with viral infections. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important etiological factors of HCC, accounting for more than 70% of cases worldwide. The risk of HCC development is greatly increased in chronic viral carriers exposed to other recognized risk factors, including exposure to aflatoxin B1, alcoholic cirrhosis and diabetes. The importance of HBV genotypes and precore or core promoter mutants remains incompletely understood. The role of HBV in tumour formation appears to be complex and may involve both direct and indirect mechanisms. Integration of HBV DNA into the host genome occurs at early steps of clonal tumour expansion, and it has been shown to induce direct insertional mutagenesis of diverse cancer-related genes in a number of cases. Chronic liver inflammation and hepatic regeneration induced by cellular immune responses may favour the accumulation of genetic alterations in infected hepatocytes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein LHBs may contribute in deregulating the cellular transcription program and proliferation control, and sensitize liver cells to carcinogenic factors. Recent genetic studies have provided insight into the mechanisms underlying viral-associated hepatocarcinogenesis. It has been shown that the rate of chromosomal alterations is significantly increased in HBV-related tumours compared with tumours associated with other risk factors. HBV might therefore play a role in enhancing genomic instability. Inactivation of p53 by mutations and regional allelic deletions is found more frequently in tumours associated with HBV infection. By contrast, HBV related tumours harbour a low rate of beta-catenin mutations. Together, these data strongly support the notion that chronic HBV infection might trigger specific oncogenic pathways, thus playing a role beyond stimulation of host immune responses and chronic necro-inflammatory liver disease.

Animals↗

PubMed2004

miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1.

These studies show that miR-122, a 22-nucleotide microRNA, is derived from a liver-specific noncoding polyadenylated RNA transcribed from the gene hcr. The exact sequence of miR-122 as well as the adjacent secondary structure within the hcr mRNA are conserved from mammalian species back to fish. Levels of miR-122 in the mouse liver increase to half maximal values around day 17 of embryogenesis, and reach near maximal levels of 50,000 copies per average cell before birth. Lewis et al. (2003) predicted the cationic amino acid transporter (CAT-1 or SLC7A1) as a miR-122 target. CAT-1 protein and its mRNA are expressed in all mammalian tissues but with lower levels in adult liver. Furthermore, during mouse liver development CAT-1 mRNA decreases in an almost inverse correlation with miR-122. Eight potential miR-122 target sites were predicted within the human CAT-1 mRNA, with six in the 3'-untranslated region. Using a reporter construct it was found that just three of the predicted sites, linked in a 400-nucleotide sequence from human CAT-1, acted with synergy and were sufficient to strongly inhibit protein synthesis and reduce mRNA levels. In summary, these studies followed the accumulation during development of miR-122 from its mRNA precursor, hcr, through to identification of what may be a specific mRNA target, CAT-1.

Animals↗

PubMed2004

[Hepatic tumors in childhood: experience on 245 tumors and review of literature].

This review on the pathology of hepatic tumors in childhood, from a personal series of 245 tumors, focuses on incidence, management, description of frequent tumors such as hepatoblastoma, fibrolamellar carcinoma, and undifferentiated sarcoma for malignant tumors, focal nodular hyperplasia, hepatocellular adenoma, and mesenchymal hamartoma for benign tumors. Malignant and benign entities of recent description, including the following: crowded, small cell undifferentiated and cholangioblastic variants of hepatoblastomas, mesenchymal hamartoma miming hepatoblastoma, liver adenoma and adenomatosis in diabete MODY3 families, gastrointestinal stromal tumor with liver metastasis associated to Carney triad, macronodules in non-cirrhotic portal fibrosis are reviewed. For each entity, the clinical presentation, the diagnostic criteria and the differential diagnosis are described. The role of immunohistochemistry and molecular biology in the diagnosis and identification of new molecular mechanisms triggered by oncogenic activation with new prognostic markers, and therapeutic targets is emphasized.

Child↗

PubMed2004

Acetylation of beta-catenin by p300 regulates beta-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 beta-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of beta-catenin for Tcf4, and the cellular Tcf4-bound pool of beta-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by beta-catenin/Tcf4 and that the cooperation between p300 and beta-catenin was severely reduced by the K345R mutation, implying that acetylation of beta-catenin plays a part in the coactivation of beta-catenin by p300. Interestingly, acetylation of beta-catenin had opposite, negative effects on the binding of beta-catenin to the androgen receptor. Our data suggest that acetylation of beta-catenin in the arm 6 domain regulates beta-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 beta-catenin transcriptional activity.

Acetylation↗

PubMed2002

Transcriptional activation of interleukin-8 by beta-catenin-Tcf4.

Nuclear translocation of beta-catenin and its association with Tcf/Lef factors are key steps in transduction of the Wnt signal, which is aberrantly activated in a variety of human cancers. In a search for new beta-catenin-Tcf target genes, we analyzed beta-catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable beta-catenin or its truncated, transactivation-deficient counterpart by means of a lentiviral vector. cDNA microarray analysis revealed a limited set of up-regulated genes, including known Wnt targets such as matrilysin and keratin-1. In this screen, we identified the CXC chemokine interleukin 8 (IL-8) as a direct target of beta-catenin-Tcf4. IL-8 is constitutively expressed in various cancers, and it has been implicated in tumor progression through its mitogenic, motogenic, and angiogenic activities. The IL-8 promoter contains a unique consensus Tcf/Lef site that is critical for IL-8 activation by beta-catenin. We show here that the p300 coactivator was required for efficient transactivation of beta-catenin on this promoter. Ectopic expression of beta-catenin in hepatoma cells promoted IL-8 secretion, which stimulated endothelial cell migration. These data define IL-8 as a Wnt target and suggest that IL-8 induction by beta-catenin might be implicated in developmental and tumorigenic processes.

Cell Movement↗

PubMed2002

Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors.

Transgenic mice expressing the c-Myc oncogene driven by woodchuck hepatitis virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To investigate genetic lesions that cooperate with Myc in liver carcinogenesis, we conducted a genome-wide scan for loss of heterozygosity (LOH) and mutational analysis of beta-catenin in 37 hepatocellular adenomas and carcinomas from C57BL/6 x castaneus F1 transgenic mice. In a subset of these tumors, chromosome imbalances were examined by comparative genomic hybridization (CGH). Allelotyping with 99 microsatellite markers spanning all autosomes revealed allelic imbalances at one or more chromosomes in 83.8% of cases. The overall fractional allelic loss was rather low, with a mean index of 0.066. However, significant LOH rates involved chromosomes 4 (21.6% of tumors), 14, 9 and 1 (11 to 16%). Interstitial LOH on chromosome 4 was mapped at band C4-C7 that contains the INK4a/ARF and INK4b loci, and on chromosome 14 at band B-D including the RB locus. In man, the homologous chromosomal regions 9p21, 13q14 and 8p21-23 are frequently deleted in liver cancer. LOH at chromosomes 1 and 14, and beta-catenin mutations (12.5% of cases) were seen only in HCCs. All tumors examined were found to be aneuploid. CGH analysis of 10 representative cases revealed recurrent gains at chromosomes 16 and 19, but losses or deletions involving mostly chromosomes 4 and 14 generally prevailed over gains. Thus, Myc activation in the liver might select for inactivation of tumor suppressor genes on regions of chromosomes 4 and 14 in a context of low genomic instability. Myc transgenic mice provide a useful model for better defining crosstalks between oncogene and tumor suppressor pathways in liver tumorigenesis.

Adenoma, Liver Cell↗

PubMed2002

Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: importance of TGF-beta signalling in the control of liver homeostasis and transformation.

The c-Met tyrosine kinase receptor and its ligand, Hepatocyte Growth Factor/ Scatter Factor, have been implicated in human cancer. We have previously described that the transgenic expression of a truncated form of human c-Met (cyto-Met) in the liver confers resistance to several apoptotic stimuli. Here we show the impact of cyto-Met expression on liver proliferation and transformation. Despite a sixfold increase of hepatocyte proliferation, adult transgenic livers displayed normal size and architecture. We present evidence showing that activation of TGF-beta1 signalling controls the liver mass in cyto-Met mice. The oncogenic potential of cyto-Met was further assessed in the context of c-Myc-induced hepatocarcinogenesis, using WHV/c-Myc transgenic mice. Co-expression of cyto-Met and c-Myc further enhanced hepatocyte proliferation and caused a dramatic acceleration of the Myc-induced tumorigenesis, leading to the emergence of hepatocarcinomas in 3-4-month-old animals. Importantly, the TGF-beta receptor type II expression was strongly downregulated in most tumours, indicating that impairment of TGF-beta1-mediated growth inhibition plays a major role in accelerated neoplastic development. The strong potential of cyto-Met for oncogenic cooperation without direct transforming activity designates cyto-Met mice as an ideal tool for studying the early steps of multistage hepatocarcinogenesis and for identification of prognostic markers of transformation.

Animals↗

PubMed2002

Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects.

Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are two different subtypes of primary tumors arising from liver parenchymal cells. These tumors differ by many histoclinical characteristics, and comparative analysis of genetic alterations in HB and HCC might provide some clues on the molecular oncogenic pathways leading to hepatocyte transformation. Recent outcomes have been provided by the assessment of global genetic changes in tumor cells, using conventional cytogenetic approaches, PCR-based microsatellite analysis and Comparative genomic Hybridization (CGH). Cytogenetic studies of HB, microsatellite analysis of HCC and recent CHG data have outlined common and distinctive characters between the two tumor types. HBs are characterized by a low number of chromosomal changes, consisting mainly of gains at chromosomes 1q, 2, 8q, 17q, and 20. By contrast, HCCs harbor multiple chromosomal abnormalities, predominantly losses, with increased chromosomal instability in tumors associated with hepatitis B virus infection. Common alterations in HB and HCC include gain of chromosomes 1q, 8q, and 17q, and loss of 4q. Another important common feature shared by the two tumor types is the frequent activation of Wnt/beta-catenin signaling by stabilizing mutations of beta-catenin. Immunohistochemical analysis of beta-catenin has demonstrated nuclear/cytoplasmic accumulation of the protein in most HBs and in more than one third of HCCs. Strikingly, beta-catenin mutations are associated with chromosomal stability in both tumor types. Together, these studies define different pathways in liver cell transformation, reflecting various developmental stages and multiple risk factors. A detailed understanding of the molecular hits underlying liver tumorigenesis, combined with clinicopathological parameters, will permit an accurate evaluation of major targets for prognostic and therapeutic intervention.

Carcinoma, Hepatocellular↗

PubMed2002

Genetic alterations and oncogenic pathways in hepatocellular carcinoma.

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 beta-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.

Carcinoma, Hepatocellular↗