Project description:The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential actors and partners in pancreatic tumourigenesis. However, the way they function is still largely unknown. We thus undertook in this work to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4. Using co-immunoprecipitation, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2. Stable Knocked-Down (KD) cellular clones for both MUC4 and ErbB2 were raised by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. This indicates that ErbB2 and MUC4, that physically interact, activate different intracellular signalling pathways to regulate biological properties of pancreatic cancer cells. Altogether, these data bring new information regarding molecular mechanisms under the control of both MUC4 and ErbB2 that will have to be taken into account for developing efficient targeting of both proteins in order to slow down/stop pancreatic tumourigenesis. profiling of pancreatic cells depleted for ErbB2 and MUC4
Project description:Depleting lncEPAT in GBM cells leads to altered gene expression profile lncRNAs are aberrantly expressed in different cancers; recent discoveries showed that lncRNAs participate in cancer signaling pathways via interacting with proteins, nucleotides, and lipids. Our goal is to characterize the role of an oncogenic lncRNA (lncEPAT) that mediates the integration of the dysregulated EGFR pathway with H2A deubiquitination in glioblastoma tumorigenesis.
Project description:Dysregulated RPB1 is a critical oncogenic hub that drives overgrowth hijacking an array of oncogenic and anti-apoptosis factors.Targeting RPB1 leads to potent regression of human refractory AML in mouse models.
Project description:Mutations in the chromatin remodeller CHD7 cause CHARGE syndrome (CS). Importantly, children with CS exhibit moderate to severe neurological and behaviour symptoms including autism. However, the neural substrates underlying these symptoms remain largely unknown. Here we show that zebrafish chd7 mutant display a nighttime hyperactivity behavioural phenotype and exhibit altered number and positioning of GABAergic neurons in brain regions. Using a transcriptomic approach, we identified many genes involved in cell adhesion, migration and receptor signalling that are dysregulated in the chd7 brain. We also show an abnomal hyperactivation of ERK signalling contributing to the GABAergic defects. A phenotype-based screen of 3850 compounds identifies a lead compound, ephedrine that ameliorates GABAergic and behavioural anomalies in chd7 animals. Our study identifies CHD7 as critical regulator of GABAergic network development. Importantly, we provide novel insight into the mechanisms underlying the neurological deficits in CS and identify a new therapeutic for CS-associated neurobehavioural symptoms.
Project description:Low protein (LP) during gestation leads to low birth weight and poor fetal growth, with altered islet development and glucose intolerance in adulthood. Additionally, LP offspring fail to regenerate their β-cells following depletion with streptozotocin (STZ), in contrast to control-fed offspring that are capable of β-cell regeneration. Our objective was to identify genes and signalling pathways that may be critically altered in LP offspring rendering them susceptible to develop long term glucose intolerance and decreased β-cell plasticity.
Project description:p53 mutation and its subsequent loss of function along with gain of oncogenic functions is associated with cancer. However, the exact mechanism of how altered p53 acts as an oncogene is not clear yet. Recently, it was suggested that p53 aggregation and amyloid formation leads to both loss of tumor suppressive function and gain of oncogenic functions in cells. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloid aggregates show enhanced survival, apoptotic resistance with increased proliferation and migration rate. We further establish the tumorigenic potential of p53 amyloid containing cells in a mice xenograft model. Furthermore, these tumors tested positive for p53 amyloid aggregates. Comprehensive gene-expression analysis suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor suppressor associated genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to initiation of tumor development.