111 research outputs found
Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
No full textThe tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.</p
Neuronal programming by microbiota regulates intestinal physiology
No full textNeural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders1. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility2-5, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.sponsorship: We thank the Crick Science Technology Platforms, the University of Bern FACSLab and the Bern Clean Mouse Facility for expert support; R. Lasrado and S.-H. Chng for assistance with tissue dissection; M. Shapiro for bioinformatic input; C. Schiering for useful advice; all members of the Pachnis laboratory for insightful comments on the manuscript and discussions; and M. D'Amato for insightful comments on the manuscript. Y.O. was supported by an EMBO long-term fellowship (ALTF 1214-2015), travel grants from Boehringer Ingelheim Fonds and the Society for Mucosal Immunology (SMI); he is currently supported by an HFSP postdoctoral fellowship (LT000176/2016). This work was supported by the Medical Research Council (MRC) and The Francis Crick Institute (which receives funding from the MRC, Cancer Research UK and the Wellcome Trust). V.P. was also funded by BBSRC (BB/L022974) and the Wellcome Trust (212300/Z/18/Z). (EMBO long-term fellowship|ALTF 1214-2015, Boehringer Ingelheim Fonds, Society for Mucosal Immunology (SMI), HFSP postdoctoral fellowship|LT000176/2016, Medical Research Council (MRC), Francis Crick Institute (MRC), Francis Crick Institute (Cancer Research UK), Francis Crick Institute (Wellcome Trust), BBSRC|BB/L022974, Wellcome Trust|212300/Z/18/Z, Wellcome Trust|212300/Z/18/Z, BBSRC|BB/L022974/1)status: Publishe
Next-Generation Sequencing: Application in Liver Cancer—Past, Present and Future?
No full textHepatocellular Carcinoma (HCC) is the third most deadly malignancy worldwide characterized by phenotypic and molecular heterogeneity. In the past two decades, advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. More recently, improvements of sophisticated next-generation sequencing (NGS) technologies have enabled complete and cost-efficient analyses of cancer genomes at a single nucleotide resolution and advanced into valuable tools in translational medicine. Although the use of NGS in human liver cancer is still in its infancy, great promise rests in the systematic integration of different molecular analyses obtained by these methodologies, i.e., genomics, transcriptomics and epigenomics. This strategy is likely to be helpful in identifying relevant and recurrent pathophysiological hallmarks thereby elucidating our limited understanding of liver cancer. Beside tumor heterogeneity, progress in translational oncology is challenged by the amount of biological information and considerable “noise” in the data obtained from different NGS platforms. Nevertheless, the following review aims to provide an overview of the current status of next-generation approaches in liver cancer, and outline the prospects of these technologies in diagnosis, patient classification, and prediction of outcome. Further, the potential of NGS to identify novel applications for concept clinical trials and to accelerate the development of new cancer therapies will be summarized
Weight gain in mid-childhood and its relationship with the fast food environment
No full text© The Author 2017. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. Background Childhood obesity is a serious public health issue. Understanding environmental factors and their contribution to weight gain is important if interventions are to be effective. Aims The purpose of this research was to assess the relationship between weight gain in children and accessibility of fast-food outlets. Methods A longitudinal sample of 1577 children was created using two time points from the National Child Measurement Programme in South Gloucestershire (2006/7 and 2012/13). A spatial analysis was conducted using a weighted accessibility score on the number of fast-food outlets within a 1-km network radius of each child's residence to quantify access to fast food. Results The mean accessibility score for all children was 0.73 (standard deviation: 1.14). Fast-food outlets were more prevalent in areas of deprivation. A moderate association was found between deprivation score and accessibilty score (r = 0.4, P 50 percentile points) compared to children who had no access to fast-food outlets. Conclusions This paper supports previous research that fast-food outlets are more prevalent in areas of deprivation and presents new evidence on fast-food outlets as a potential contributor towards weight gain in mid-childhood
Author Correction:YAP1/TAZ drives ependymoma-like tumour formation in mice
No full textAn amendment to this paper has been published and can be accessed via a link at the top of the paper.</p
ERK-Induced Activation of TCF Family of SRF Cofactors Initiates a Chromatin Modification Cascade Associated with Transcription
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Abstract 2987: Identification of new combination therapies for lung tumors harboring KRAS mutations
No full textSRF co-factors control the balance between cell proliferation and contractility
No full textInternational audienceGraphical Abstract Highlights d Integrated ChIP-seq Hi-C analysis identifies over 700 TCF-dependent SRF target genes d Over 60% of TPA-inducible gene transcription is TCF-dependent d TCF-dependent transcription potentiates cell proliferation d TCF/MRTF competition for SRF determines contractility and pro-invasive behavio
Metastatic-niche labelling reveals parenchymal cells with stem features.
No full textDirect investigation of the early cellular changes induced by metastatic cells within the surrounding tissue remains a challenge. Here we present a system in which metastatic cancer cells release a cell-penetrating fluorescent protein, which is taken up by neighbouring cells and enables spatial identification of the local metastatic cellular environment. Using this system, tissue cells with low representation in the metastatic niche can be identified and characterized within the bulk tissue. To highlight its potential, we applied this strategy to study the cellular environment of metastatic breast cancer cells in the lung. We report the presence of cancer-associated parenchymal cells, which exhibit stem-cell-like features, expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. In ex vivo assays, lung epithelial cells acquire a cancer-associated parenchymal-cell-like phenotype when co-cultured with cancer cells and support their growth. These results highlight the potential of this method as a platform for new discoveries
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