35 results on '"Michael Boutros"'
Search Results
2. Borrow Now, Pay Even Later: A Quantitative Analysis of Student Debt Payment Plans
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Michael Boutros, Nuno Clara, and Francisco Gomes
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
3. CRISPR/Cas9 for cancer research and therapy
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Johannes Betge, Tianzuo Zhan, Matthias P. Ebert, Michael Boutros, and N Rindtorff
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Gene Editing ,0301 basic medicine ,Cancer Research ,Genome, Human ,Cas9 ,Research ,Cancer ,Synthetic lethality ,Biology ,medicine.disease ,Genome ,Genome engineering ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug development ,Neoplasms ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Humans ,CRISPR ,CRISPR-Cas Systems ,Functional genomics - Abstract
CRISPR/Cas9 has become a powerful method for making changes to the genome of many organisms. First discovered in bacteria as part of an adaptive immune system, CRISPR/Cas9 and modified versions have found a widespread use to engineer genomes and to activate or to repress the expression of genes. As such, CRISPR/Cas9 promises to accelerate cancer research by providing an efficient technology to dissect mechanisms of tumorigenesis, identify targets for drug development, and possibly arm cells for cell-based therapies. Here, we review current applications of the CRISPR/Cas9 technology for cancer research and therapy. We describe novel Cas9 variants and how they are used in functional genomics to discover novel cancer-specific vulnerabilities. Furthermore, we highlight the impact of CRISPR/Cas9 in generating organoid and mouse models of cancer. Finally, we provide an overview of the first clinical trials that apply CRISPR/Cas9 as a therapeutic approach against cancer.
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- 2019
4. Evaluating the Impact of Economic Impact Payments
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Michael Boutros
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Aggregate expenditure ,media_common.quotation_subject ,Labor income ,Demographic economics ,Business ,Economic impact analysis ,Census ,Payment ,media_common - Abstract
As part of the CARES Act, the IRS distributed $300 billion in Economic Impact Payments (EIPs) directly to US households. In the Census Bureau’s Household Pulse Survey, almost 75% of households receiving an EIP reported using it to mostly pay for expenses. Separating respondents based on labor income interruptions, 84% of unemployed households reported mostly spending their EIPs, compared to 63% of employed households, suggesting that the benefits of more targeted direct transfers may have been limited, especially at the expense of timeliness. Overall, I conclude that Economic Impact Payments played an important role in stabilizing aggregate spending.
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- 2020
5. Microenvironmental innate immune signaling and cell mechanical responses promote tumor growth
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Michael Boutros, Jun Zhou, and Erica Valentini
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MAP Kinase Kinase 4 ,Cell ,Biology ,medicine.disease_cause ,Mechanotransduction, Cellular ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Neoplasms ,Cell Adhesion ,Tumor Microenvironment ,medicine ,Animals ,Drosophila Proteins ,Humans ,Cell adhesion ,Molecular Biology ,Tissue homeostasis ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Innate immune system ,Cell growth ,NF-kappa B ,Cell Biology ,Immunity, Innate ,Cell biology ,Intestines ,Disease Models, Animal ,Drosophila melanogaster ,Enterocytes ,medicine.anatomical_structure ,Stem cell ,Carrier Proteins ,Carcinogenesis ,030217 neurology & neurosurgery ,Signal Transduction ,Transcription Factors ,Developmental Biology - Abstract
Tissue homeostasis is achieved by balancing stem cell maintenance, cell proliferation and differentiation, as well as the purging of damaged cells. Elimination of unfit cells maintains tissue health; however, the underlying mechanisms driving competitive growth when homeostasis fails, for example, during tumorigenesis, remain largely unresolved. Here, using a Drosophila intestinal model, we find that tumor cells outcompete nearby enterocytes (ECs) by influencing cell adhesion and contractility. This process relies on activating the immune-responsive Relish/NF-κB pathway to induce EC delamination and requires a JNK-dependent transcriptional upregulation of the peptidoglycan recognition protein PGRP-LA. Consequently, in organisms with impaired PGRP-LA function, tumor growth is delayed and lifespan extended. Our study identifies a non-cell-autonomous role for a JNK/PGRP-LA/Relish signaling axis in mediating death of neighboring normal cells to facilitate tumor growth. We propose that intestinal tumors "hijack" innate immune signaling to eliminate enterocytes in order to support their own growth.
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- 2021
6. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver
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Jingjing Shi, Moritz Jakab, Mathias Heikenwalder, Shalev Itzkovitz, Martin Schneider, Indrabahadur Singh, Shubhada Rajabhau Kulkarni, Paula Argos Vélez, Michael Boutros, Maria Riedel, Ki Hong Lee, Thomas Ruppert, Sudhakar Chintharlapalli, Hellmut G. Augustin, Dominic Helm, Carleen Spegg, Guanxiong Wang, Marziyeh Komeili, Christine Schaeffer-Reiss, Shani Ben-Moshe, and Donato Inverso
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Proteomics ,Resource ,Quantitative proteomics ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Receptor tyrosine kinase ,transcriptomics ,Wnt ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,liver endothelial cell (L-EC) ,Humans ,Regeneration ,Endothelium ,RNA-Seq ,Phosphorylation ,Wnt Signaling Pathway ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Phosphoproteomics ,Wnt signaling pathway ,Endothelial Cells ,Gene Expression Regulation, Developmental ,phosphoproteomics ,vascular zonation ,Tyrosine phosphorylation ,Cell Biology ,Flow Cytometry ,Phosphoproteins ,Liver Regeneration ,Cell biology ,Tie2 ,Liver ,Tie1 ,chemistry ,angiocrine factors ,Proteome ,Hepatocytes ,biology.protein ,Single-Cell Analysis ,Transcriptome ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Summary Single-cell transcriptomics (scRNA-seq) has revolutionized the understanding of the spatial architecture of tissue structure and function. Advancing the “transcript-centric” view of scRNA-seq analyses is presently restricted by the limited resolution of proteomics and genome-wide techniques to analyze post-translational modifications. Here, by combining spatial cell sorting with transcriptomics and quantitative proteomics/phosphoproteomics, we established the spatially resolved proteome landscape of the liver endothelium, yielding deep mechanistic insight into zonated vascular signaling mechanisms. Phosphorylation of receptor tyrosine kinases was detected preferentially in the central vein area, resulting in an atypical enrichment of tyrosine phosphorylation. Prototypic biological validation identified Tie receptor signaling as a selective and specific regulator of vascular Wnt activity orchestrating angiocrine signaling, thereby controlling hepatocyte function during liver regeneration. Taken together, the study has yielded fundamental insight into the spatial organization of liver endothelial cell signaling. Spatial sorting may be employed as a universally adaptable strategy for multiomic analyses of scRNA-seq-defined cellular (sub)-populations., Graphical abstract, Highlights • ScRNA-seq-guided spatial sort enables multiomic dissection of the liver vasculature • Liver sinusoidal endothelial cells have a hybrid vascular-lymphatic phenotype • Tyrosine phosphorylation of endothelial cell molecules is enriched on central vein • Endothelial Tie1 shapes hepatic Wnt signal zonation and promotes liver regeneration, Inverso, Shi et al. generate a multiomic encyclopedia of liver endothelial cells (L-ECs) with spatial resolution of transcriptome, proteome, and phosphoproteome. The study provides insight into liver vascular zonation and a template for scRNA-seq-data-guided spatial proteome and phosphoproteome analyses.
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- 2021
7. An RNAi Screen Reveals an Essential Role for HIPK4 in Human Skin Epithelial Differentiation from iPSCs
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Michael Boutros, Daniel Novak, Hans C. Volz, Jochen Utikal, Lionel Larribère, Petra Boukamp, Karla Arévalo, Marta Galach, and Hans Jürgen Stark
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keratinocytes ,0301 basic medicine ,skin ,Cellular differentiation ,Induced Pluripotent Stem Cells ,Population ,HIPK4 ,Human skin ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Article ,Cell Line ,03 medical and health sciences ,Organ Culture Techniques ,RNA interference ,Genetics ,Humans ,Gene silencing ,Gene Silencing ,Induced pluripotent stem cell ,education ,development ,lcsh:QH301-705.5 ,Cells, Cultured ,RNAi screen ,lcsh:R5-920 ,education.field_of_study ,iPSC ,Cell Differentiation ,Epithelial Cells ,differentiation ,Cell Biology ,High-Throughput Screening Assays ,Cell biology ,Enzyme Activation ,stem cell ,030104 developmental biology ,organotypic culture ,lcsh:Biology (General) ,Cell culture ,RNA Interference ,Stem cell ,epithelium ,lcsh:Medicine (General) ,Developmental Biology - Abstract
Summary Molecular mechanisms responsible for the development of human skin epithelial cells are incompletely understood. As a consequence, the efficiency to establish a pure skin epithelial cell population from human induced pluripotent stem cells (hiPSCs) remains poor. Using an approach including RNAi and high-throughput imaging of early epithelial cells, we identified candidate kinases involved in their differentiation from hiPSCs. Among these, we found HIPK4 to be an important inhibitor of this process. Indeed, its silencing increased the amount of generated skin epithelial precursors at an early time point, increased the amount of generated keratinocytes at a later time point, and improved growth and differentiation of organotypic cultures, allowing for the formation of a denser basal layer and stratification with the expression of several keratins. Our data bring substantial input regarding regulation of human skin epithelial differentiation and for improving differentiation protocols from pluripotent stem cells., Highlights • High-throughput RNAi screen setup during human skin epithelial differentiation • Identification of HIPK4 as a crucial blocker of human skin epithelial differentiation • Improvement of human organotypic epithelial cultures after HIPK4 silencing, In this article, Larribère and colleagues establish a high-throughput RNAi screen on induced pluripotent stem cell-derived epithelial cells. This screen led to the identification of HIPK4 as a crucial blocker of human skin epithelial differentiation. Indeed, HIPK4 silencing increased the amount of early generated skin epithelial precursors, increased the amount of generated keratinocytes, and improved the differentiation of organotypic cultures.
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- 2017
8. Immune cell recruitment in teratomas is impaired by increased Wnt secretion
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Fabian Brunk, Michael Boutros, Eugen Rempel, Dyah L. Dewi, Jennifer Hundshammer, and Iris Augustin
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0301 basic medicine ,Embryonic stem cells ,Mice, SCID ,Tumor initiation ,Biology ,Malignant transformation ,Mice ,03 medical and health sciences ,Animals ,Humans ,Cell Proliferation ,Medicine(all) ,Tumor microenvironment ,Teratoma ,Wnt signaling pathway ,Cell Differentiation ,LRP5 ,Cell Biology ,General Medicine ,Wnt signaling ,Embryonic stem cell ,Wnt Proteins ,Immunosurveillance ,Immune surveillance ,030104 developmental biology ,Tumor progression ,Immunology ,Cancer research ,Developmental Biology - Abstract
Wnt signaling plays a central role in tumor initiation and tumor progression. Mutations in Wnt pathway components, such as the tumor suppressor APC, lead to malignant transformation. While previous studies focused on Wnt-related changes in cancer cells, the impact of aberrant Wnt signaling on the tumor microenvironment is only beginning to emerge. In order to investigate the role of increased Wnt secretion on tumor growth and the microenvironment, we generated a novel germ cell tumor model by overexpressing the Wnt secretion factor Evi/Wls in mouse embryonic stem cells. Evi-overexpressing teratoma were characterized by enhanced tumor growth in supporting a tumor-promoting role of Wnt secretion. Interestingly, enhanced Evi expression correlated with impaired immune cell recruitment. Specifically, T- and B-cell infiltration was reduced in Evi-overexpressing teratomas, which was independent of teratoma size and differentiation. Our study suggests that Wnt secretion impairs immunosurveillance. Since immune cell infiltration has been shown to have prognostic value, the levels of secreted Wnt activity might impact the efficiency of cancer immunotherapy.
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- 2016
9. Household Finances and Fiscal Stimulus in 2008
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Michael Boutros
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Consumption (economics) ,Credit card ,Stimulus (economics) ,Debt ,media_common.quotation_subject ,Economics ,Balance sheet ,Monetary economics ,Survey of Income and Program Participation ,Payment ,Marginal propensity to consume ,media_common - Abstract
Using detailed household-level data from the Survey of Income and Program Participation, the ratio of credit card debt to income is found to be the most important balance sheet item in determining household usage of stimulus funds in 2008, adding to existing evidence that borrowing constraints are functions of debt-to-income ratios. Borrowing constrained households, often predicted to be the group with the largest propensity to consume out of stimulus funds, were the most likely to use stimulus payments to repay debt instead of increase consumption. This behavior is consistent with the fact that household credit supply was tightening at the same time that stimulus payments were being distributed, forcing households, especially those near their borrowing constraints, to deleverage.
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- 2019
10. Pooled In Vitro and In Vivo CRISPR-Cas9 Screening Identifies Tumor Suppressors in Human Colon Organoids
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Ewelina Czlonka, Khalil Abou-El-Ardat, Birgitta E. Michels, Tahmineh Darvishi, Sebastian Wagner, Barbara I. Streibl, Hind Medyouf, Henner F. Farin, Constantin Menche, Mohammed H. Mosa, Jan Winter, Tianzuo Zhan, and Michael Boutros
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Tumor suppressor gene ,Colon ,Context (language use) ,Computational biology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Organoid ,Humans ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Genes, Tumor Suppressor ,030304 developmental biology ,Genetic testing ,0303 health sciences ,Tumor microenvironment ,medicine.diagnostic_test ,Genetic heterogeneity ,Cell Biology ,Organoids ,Molecular Medicine ,CRISPR-Cas Systems ,Functional genomics ,030217 neurology & neurosurgery - Abstract
Summary Colorectal cancer (CRC) is characterized by prominent genetic and phenotypic heterogeneity between patients. To facilitate high-throughput genetic testing and functional identification of tumor drivers, we developed a platform for pooled CRISPR-Cas9 screening in human colon organoids. Using transforming growth factor β (TGF-β) resistance as a paradigm to establish sensitivity and scalability in vitro, we identified optimal conditions and strict guide RNA (gRNA) requirements for screening in 3D organoids. We then screened a pan-cancer tumor suppressor gene (TSG) library in pre-malignant organoids with APC−/−;KRASG12D mutations, which were xenografted to study clonal advantages in context of a complex tumor microenvironment. We identified TGFBR2 as the most prevalent TSG, followed by known and previously uncharacterized mediators of CRC growth. gRNAs were validated in a secondary screen using unique molecular identifiers (UMIs) to adjust for clonal drift and to distinguish clone size and abundance. Together, these findings highlight a powerful organoid-based platform for pooled CRISPR-Cas9 screening for patient-specific functional genomics.
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- 2020
11. ‘Corrigendum to 'Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia' [Molecular Metabolism 5 (2) (2015) 67–78]’
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Marc N. Hirt, Mauricio Berriel Diaz, Christian U. Oeing, Norbert Gretz, Michaela Schäfer, Thomas Eschenhagen, Hugo A. Katus, Lorenz H. Lehmann, Karin Müller-Decker, Thilo Hackert, Ralf Bauer, Tessa Werner, H. Christian Volz, Oliver Strobel, Katrin Eichelbaum, Jeroen Krijgsveld, Maria Rohm, Stephan Herzig, Michael Boutros, Daniela Sohn, Ezgi Baysal-Temel, Johannes Backs, and Carsten Sticht
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Regulation of gene expression ,lcsh:Internal medicine ,Cell Biology ,Biology ,medicine.disease ,Phenotype ,Cachexia ,Cell biology ,Transcriptome ,Atrophy ,Secretory protein ,Cell culture ,Gene expression ,medicine ,lcsh:RC31-1245 ,Corrigendum ,Molecular Biology - Abstract
The authors regret that the original paper was published with an error in the supplementary data (Table 1). In order to identify tumor-secreted factors that contribute to cardiac atrophy under the condition of cancer cachexia, in the original study, we performed a differential secretome analysis comparing cell conditioned media from cachexia-inducing C26 colon carcinoma cells and non-cachexia-inducing MC38 colon carcinoma cells. Secreted proteins which were at least 2-fold more abundantly secreted from C26 cells were selected for further functional validation. Functional validation was performed by overexpressing candidate proteins in HEK293A cells and collecting the candidate-enriched cell conditioned media for assaying their atrophy-inducing potential on primary neonatal rat cardiomyocytes. In the context of subsequent studies focusing on different aspects of cancer-induced cachexia, we performed a differential transcriptomics analysis comparing RNAseq data from C26 and MC38 cells. While differential protein secretion does not necessarily need to be fully reflected by corresponding differences at the level of gene expression, we were still surprised about the lack of congruency between the corresponding regulation of gene expression and protein secretion. Surprisingly, for the overlap of genes and proteins being differentially regulated between C26 and MC38 cells (regardless of the direction of change), we found a significant negative correlation between differential gene expression and differential protein secretion (Corrigendum Figure 1 A). In order to elucidate the basis of this unexpected finding, we decided to repeat the differential secretome analysis in the same manner as it has been performed in the original study. Notably, the comparison between the secretome analyses (old vs new) revealed a remarkably strong negative correlation concerning the difference in protein secretion between C26 and MC38 cells (Corrigendum Figure 1B). Furthermore, when we then compared the new secretome analysis with the differences in the transcription between C26 and MC38 cells, there was a highly significant positive correlation (Corrigendum Figure 1C). The found consistency for the differences between the cell lines at distinct levels of regulation (transcription vs secretion) suggested that these datasets were correctly associated, in contrast to the previous comparison with the original differential secretome analysis. Taken together, these new analyses strongly indicate that in the original (old) secretome analysis, a swap in the sample allocation must have occurred, either during sample preparation, the subsequent proteomic or data analysis. Despite extensive evaluation of the respective experiment records, it was not possible to detect at which exact point in the course of the experimental work this mistake was made. Remarkably enough, the high-throughput functional validation of 109 candidates performed in the original study (original manuscript Figure 3C), using selected candidates now considered to be more abundantly secreted from non-cachexia-inducing MC38 instead of cachexia-inducing C26 cells, still revealed a set of candidates showing the expected atrophy effects upon treatment of primary cardiomyocytes with the respective candidate-enriched conditioned media. These effects were comparable to the effects of C26 conditioned medium on cardiomyocyte atrophy (original Figure 2A and B) and were therefore applied as primary selection criterion for putative cachexokines (mediators of cachexia). Additionally, further analysis selected a subset of 7 candidates which, similar to C26 conditioned medium, increased the fatty acid oxidation rate in neonatal rat cardiomyocytes treated with candidate-enriched medium (original Figure 4A). We speculate that the high-throughput functional analysis, albeit being based on an erroneous initial secretome analysis, contained a sufficient high number of protein candidates in order to contain protein factors which eventually turned out to be still relevant with respect to their capability to mediate a specific component of the cachexia phenotype (cardiomyocyte atrophy). This is exemplified by the main candidate Ataxin-10 (Atxn10), for which we could confirm elevated levels in different models of experimental cachexia, including C26 tumor-bearing mice but not in MC38 tumor-bearing mice (original Figure 5A–D). In a model pancreatic of cancer based on orthotopic cell implantation, circulating Atxn10 levels closely correlated with the degree of weight loss (Figure 5E and F). Finally, we found Atxn10 levels to be elevated in cancer patients with cachexia compared to weight-stable patients (Figure 5G). Therefore, we would like to emphasize that the majority of data provided in the publication is still correct. We apologize for any inconvenience that might have resulted from providing incorrect differential secretome data as supplemental material of the study and now provide the data of the new and correct differential secretome analysis (Corrigendum supplemental data).
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- 2020
12. Decoding the Regulatory Logic of the Drosophila Male Stem Cell System
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Fani Papagiannouli, Jan U. Lohmann, Olga Ermakova, Srividya Tamirisa, Samantha Brunel, Eugen Rempel, Juliane Mundorf, Naima Ruhland, Jun Zhou, Ingrid Lohmann, Nils Trost, and Michael Boutros
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medicine.anatomical_structure ,Somatic cell ,medicine ,Soma ,Computational biology ,Stem cell ,Biology ,Genome ,Transcription factor ,Gene ,Germline ,Adult stem cell - Abstract
In the past decade, the importance of the niche to provide regulatory inputs to balance stem cell self-renewal and differentiation has become clear. However, the regulatory interplay between stem cells and their niche at the whole genome level is still poorly understood. To elucidate the mechanisms controlling stem cells and their progenies as they progress through their developmental program at the transcriptional level, we recorded the regulatory program of two independent cell lineages in the Drosophila testis stem cell model. To this end, we identified genes active in the soma or germline as well as genome-wide binding profiles of two essential transcription factors, Zfh-1 and Abd-A, expressed in somatic support cells and crucial for fate acquisition of both cell lineages. Our data identified key roles for TOR signalling, signal processing V-ATPase proton pumps and the nuclear transport engaged nucleoporins and we demonstrate their importance in controlling germline maintenance, proliferation and differentiation from the support side. To make our dataset publicly available and support quick and intuitive data mining, we generated an interactive online analysis tool. Applying our tool for comparative analysis, we uncovered conserved core gene sets of adult stem cells across species boundaries. We have tested the functional relevance of these genes in the Drosophila testis and intestine and find a striking over-representation of stem cell defects when the corresponding genes were depleted. In summary, our dataset and interactive platform represents a versatile tool for identifying novel gene networks active in diverse stem cell types and provides a valuable resource for elucidating the multifaceted regulatory inputs required to guide proper stem cell behaviour.
- Published
- 2018
13. A screening for novel immune-checkpoints identifies a serine/threonine kinase to confer immune resistance in multiple myeloma
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M. Witzens-Harig, V. Volpin, Michael Boutros, M. Ehrenschwender, T. Michels, A. Sorrentino, M. Ditz, A.N. Menevse, Philipp Beckhove, and G. Knoll
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Serine/threonine-specific protein kinase ,Cancer Research ,Immune system ,Oncology ,medicine ,Cancer research ,Immune resistance ,Biology ,medicine.disease ,Multiple myeloma - Published
- 2019
14. Dpp/Gbb signaling is required for normal intestinal regeneration during infection
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Devanjali Dutta, Anna Lisa Boettcher, Grainne Kerr, Sebastian Florescu, Lichao Luo, Yu Cai, Bruce A. Edgar, Jun Zhou, and Michael Boutros
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medicine.medical_specialty ,animal structures ,Notch signaling pathway ,EC differentiation ,Stem cells ,Biology ,Dpp/Gbb signaling ,Transforming Growth Factor beta ,Precursor cell ,Internal medicine ,medicine ,Animals ,Drosophila Proteins ,Regeneration ,Progenitor cell ,Intestinal Mucosa ,Molecular Biology ,Tissue homeostasis ,Gene Library ,Microscopy, Confocal ,Cell growth ,Reverse Transcriptase Polymerase Chain Reaction ,Regeneration (biology) ,Gene Expression Profiling ,Muscles ,High-Throughput Nucleotide Sequencing ,Cell Differentiation ,Cell Biology ,Flow Cytometry ,Intestinal epithelium ,Cell biology ,Endocrinology ,Enterocytes ,Gene Expression Regulation ,Drosophila ,Stem cell ,Infection ,Signal Transduction ,Developmental Biology - Abstract
Maintaining tissue homeostasis is a critical process during infection and inflammation. Tissues with a high intrinsic turnover, such as the intestinal epithelium, must launch a rapid response to infections while simultaneously coordinating cell proliferation and differentiation decisions. In this study, we searched for genes required for regeneration of the Drosophila intestine, and thereby affecting overall organism survival after infection with pathogenic bacteria. We found that Dpp/Gbb (BMP) signaling is essential for normal midgut regeneration, and that infection induces the BMP signaling ligands Dpp and Gbb. We demonstrate that Dpp is induced in visceral muscle and required for signaling activation. Subsequently, Gbb is induced in enterocytes after oral infection. Loss-of Dpp signaling in ISCs and transient committed progenitors called enteroblasts (EBs), or in EBs alone, led to a blockage in EC differentiation or maturation. Furthermore, our data show that down-regulation of Dpp signaling in the precursor cells including EBs also resulted in an increased number of abnormally small Pdm1-positive cells, suggesting a role of Dpp/Gbb signaling in EC growth. In addition, we show that Dpp/Gbb signaling acted downstream or in parallel to the Notch pathway to promote EC differentiation and growth. Our results suggest that Dpp/BMP signaling plays an important role in EBs to maintain tissue integrity and homeostasis during pathogenic infections.
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- 2015
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15. Secretion and extracellular space travel of Wnt proteins
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Julia Christina Gross and Michael Boutros
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Neurodegeneration ,Wnt signaling pathway ,Gene Expression Regulation, Developmental ,LRP6 ,Cell Differentiation ,LRP5 ,Biology ,Endoplasmic Reticulum ,Exosomes ,medicine.disease ,Microvesicles ,Cell biology ,Wnt Proteins ,Genetics ,Extracellular ,medicine ,Animals ,Humans ,Secretion ,Stem cell ,Extracellular Space ,Hydrophobic and Hydrophilic Interactions ,Wnt Signaling Pathway ,Developmental Biology - Abstract
Wnt signaling pathways control many processes during development, stem cell maintenance and homeostasis, and their aberrant regulation has been linked to diseases in man including diabetes, neurodegeneration and cancer. Wnts are hydrophobic proteins, however, quite paradoxically, they can travel over distances to induce cell-type specific responses. While there has been an initial focus on elucidating the intracellular signaling cascade, discoveries in the past few years have shed light on a highly complex, and regulated secretory process that guides Wnt proteins through the exocytic pathway. Wnt proteins are at least in portion packaged onto extracellular carriers such as exosomes. Similar to dysregulation of components in the Wnt receiving cell, failure to regulate Wnt secretion has been linked to cancer. Here, we review recent discoveries on factors and processes implicated in Wnt secretion.
- Published
- 2013
16. Control of Proinflammatory Gene Programs by Regulated Trimethylation and Demethylation of Histone H4K20
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Michael Boutros, Norbert Perrimon, Joshua D. Stender, Minna U. Kaikkonen, Christopher K. Glass, Kevin Do, Wen Liu, Gabriel Pascual, Michael G. Rosenfeld, and Nathanael J. Spann
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Biology ,SAP30 ,Methylation ,Models, Biological ,Article ,Cell Line ,Histones ,Histone H4 ,Mice ,Histone methylation ,Histone H2A ,Animals ,Humans ,Histone code ,Promoter Regions, Genetic ,Molecular Biology ,Inflammation ,Histone deacetylase 2 ,Macrophages ,NF-kappa B ,Histone-Lysine N-Methyltransferase ,Cell Biology ,Toll-Like Receptor 4 ,HEK293 Cells ,Gene Expression Regulation ,Histone methyltransferase ,Histone Methyltransferases ,Cancer research ,Drosophila ,Heterochromatin protein 1 ,Co-Repressor Proteins ,Signal Transduction - Abstract
Regulation of genes that initiate and amplify inflammatory programs of gene expression is achieved by signal-dependent exchange of co-regulator complexes that function to read, write and erase specific histone modifications linked to transcriptional activation or repression. Here, we provide evidence for the role of trimethylated histone H4 lysine 20 (H4K20me3) as a repression checkpoint that restricts expression of toll like receptor 4 (TLR4) target genes in macrophages. H4K20me3 is deposited at the promoters of a subset of these genes by the SMYD5 histone methyltransferase through its association with NCoR corepressor complexes. Signal-dependent erasure of H4K20me3 is required for effective gene activation and is achieved by NF-κB-dependent delivery of the histone demethylase PHF2. Liver X receptors antagonize TLR4-dependent gene activation by maintaining NCoR/SMYD5-mediated repression. These findings reveal a histone H4K20 tri-methylation/de-methylation strategy that integrates positive and negative signaling inputs that control immunity and homeostasis.
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- 2012
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17. A PP4 Holoenzyme Balances Physiological and Oncogenic Nuclear Factor-Kappa B Signaling in T Lymphocytes
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Felice Frey, Nina Booken, Markus Brechmann, Thomas Mock, Wolfgang W. Müller, Peter H. Krammer, Rüdiger Arnold, Nicole Weit, Guido H. Wabnitz, Michael Boutros, Yvonne Samstag, Jan P. Nicolay, Dorothee Nickles, Claus Detlev Klemke, Michael K. Kiessling, Rebecca Breuer, and Marco Herling
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Kinase ,T cell ,Cellular differentiation ,Phosphatase ,Immunology ,IκB kinase ,Biology ,Cell biology ,medicine.anatomical_structure ,Infectious Diseases ,Downregulation and upregulation ,Biochemistry ,medicine ,Phosphorylation ,Immunology and Allergy ,Signal transduction - Abstract
SummarySignal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas.
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- 2012
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18. Wnt/Frizzled Signaling Requires dPRR, the Drosophila Homolog of the Prorenin Receptor
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Bisei Ohkawara, Christof Niehrs, Tina Buechling, Kerstin Spirohn, Varun Chaudhary, Kerstin Bartscherer, and Michael Boutros
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Receptor complex ,Frizzled ,Xenopus ,Receptors, Cell Surface ,DEVBIO ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell polarity ,Animals ,Wings, Animal ,Prorenin Receptor ,Cells, Cultured ,chemistry.chemical_classification ,Agricultural and Biological Sciences(all) ,Convergent extension ,Biochemistry, Genetics and Molecular Biology(all) ,Wnt signaling pathway ,Cell Polarity ,LRP6 ,Epithelial Cells ,LRP5 ,Gastrula ,Frizzled Receptors ,Dishevelled ,Cell biology ,Wnt Proteins ,chemistry ,SIGNALING ,Drosophila ,RNA Interference ,General Agricultural and Biological Sciences ,Signal Transduction - Abstract
SummaryWnt/Wg signaling pathways are of key importance during development and disease [1–4]. Canonical and noncanonical Wnt/Frizzled (Fz) pathways share a limited number of signaling components that are part of the membrane proximal signaling complex. In Drosophila, Fz [5–7] and Dishevelled (Dsh) [8, 9] are the only two components known to be involved in both Wnt/β-catenin and planar cell polarity (PCP) signaling. PCP signaling is required for the planar polarization of epithelial cells [10, 11], which occurs, for instance, during hair orientation and gastrulation in vertebrates [12]. Both pathways have been studied intensively in the past years. However, it still remains unresolved whether additional components are required at the receptor complex. Here we identify the Drosophila homolog of the mammalian prorenin receptor (dPRR) as a conserved modulator of canonical Wnt/β-cat and Fz/PCP signaling. We show that dPRR depletion affects Wg target genes in cultured cells and in vivo. PRR is required for epithelial planar polarity in Drosophila and for convergent extension movements in Xenopus gastrulae. Furthermore, dPRR binds to Fz and Fz2 receptors. In summary, our data suggest that dPRR has an evolutionarily conserved role at the receptor level for activation of canonical and noncanonical Wnt/Fz signaling pathways.
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- 2010
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19. FABP5 RNA expression as potential marker in TMPRSS2:ERG fusion negative prostate cancer
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J. von Hardenberg, M.S. Michel, Maria Gottschalt, Thomas Stefan Worst, Sarah Wahby, Cleo-Aron Weis, Katja Nitschke, Michael Boutros, Frank Waldbillig, Abdallah Abdelhadi, and Philipp Erben
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Prostate cancer ,Rna expression ,business.industry ,Urology ,medicine ,Cancer research ,medicine.disease ,business ,TMPRSS2 ,Erg - Published
- 2018
20. Widespread Rewiring of Genetic Networks upon Cancer Signaling Pathway Activation
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Maximilian Billmann, Varun Chaudhary, Bernd Fischer, Michael Boutros, and Mostafa F. ElMaghraby
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genetic interactions ,0301 basic medicine ,Cell signaling ,Genes, APC ,Histology ,Biology ,epistatic mapping ,Article ,Pathology and Forensic Medicine ,law.invention ,Wnt ,03 medical and health sciences ,law ,Neoplasms ,Animals ,Drosophila Proteins ,Gene Regulatory Networks ,Wnt Signaling Pathway ,Gene ,beta Catenin ,Wnt signaling pathway ,Epistasis, Genetic ,Cell Biology ,Ligand (biochemistry) ,APC ,Cell biology ,Gene Expression Regulation, Neoplastic ,Wnt Proteins ,Multicellular organism ,Drosophila melanogaster ,030104 developmental biology ,Models, Animal ,Suppressor ,Signal transduction ,signaling ,Function (biology) ,Signal Transduction - Abstract
Summary Cellular signaling networks coordinate physiological processes in all multicellular organisms. Within networks, modules switch their function to control signaling activity in response to the cellular context. However, systematic approaches to map the interplay of such modules have been lacking. Here, we generated a context-dependent genetic interaction network of a metazoan's signaling pathway. Using Wnt signaling in Drosophila as a model, we measured >290,000 double perturbations of the pathway in a baseline state, after activation by Wnt ligand or after loss of the tumor suppressor APC. We found that genetic interactions within the Wnt network globally rewired after pathway activation. We derived between-state networks that showed how genes changed their function between state-specific networks. This related pathway inhibitors across states and identified genes required for pathway activation. For instance, we predicted and confirmed the ER-resident protein Catsup to be required for ligand-mediated Wnt signaling activation. Together, state-dependent and between-state genetic interaction networks identify responsive functional modules that control cellular pathways., Graphical Abstract, Highlights • Genetic interaction networks of Wnt signaling in three cellular states • Networks rewire upon activation of Wnt pathway by ligand or by loss of APC • Interaction profiles identify known and novel state-dependent pathway modules • State-specific and between-state profile similarity identify signaling regulators, Systematic measurement of genetic interactions between components of the Wnt pathway before and after pathway activation reveals how the pathway is rewired upon perturbation.
- Published
- 2018
21. Secretion of Wnt Ligands Requires Evi, a Conserved Transmembrane Protein
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Nadège Pelte, Kerstin Bartscherer, Dierk Ingelfinger, and Michael Boutros
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Genetics ,Phenocopy ,Wnt protein secretion ,RNA interference ,Biochemistry, Genetics and Molecular Biology(all) ,Mutant ,Wnt signaling pathway ,Secretion ,Biology ,Gene ,General Biochemistry, Genetics and Molecular Biology ,Transmembrane protein - Abstract
SummaryWnt signaling pathways are important for multiple biological processes during development and disease. Wnt proteins are secreted factors that activate target-gene expression in both a short- and long-range manner. Currently, little is known about how Wnts are released from cells and which factors facilitate their secretion. Here, we identify a conserved multipass transmembrane protein, Evenness interrupted (Evi/Wls), through an RNAi survey for transmembrane proteins involved in Drosophila Wingless (Wg) signaling. During development, evi mutants have patterning defects that phenocopy wg loss-of-function alleles and fail to express Wg target genes. evi's function is evolutionarily conserved as depletion of its human homolog disrupts Wnt signaling in human cells. Epistasis experiments and clonal analysis place evi in the Wg-producing cell. Our results show that Wg is retained by evi mutant cells and suggest that evi is the founding member of a gene family specifically required for Wg/Wnt secretion.
- Published
- 2006
- Full Text
- View/download PDF
22. Managing the genome: microRNAs in Drosophila
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Viola Gesellchen and Michael Boutros
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Genetics ,Cancer Research ,Genome ,Phylum ,ved/biology ,ved/biology.organism_classification_rank.species ,Cell Biology ,Biology ,MicroRNAs ,Drosophila melanogaster ,RNA interference ,microRNA ,Gene expression ,Animals ,Humans ,Gene silencing ,Gene Silencing ,RNA, Messenger ,Model organism ,Molecular Biology ,Gene ,Developmental Biology - Abstract
MicroRNAs (miRNAs) represent a growing class of short non-coding RNAs that regulate gene expression by post-transcriptional mechanisms. By binding to target mRNAs via stretches of sequence complementarity, microRNAs inhibit the production of target proteins or induce degradation of mRNAs. Several hundred miRNAs have recently been predicted and cloned from eukaryotic organisms as diverse as plants, invertebrates, and vertebrates. Some miRNAs were shown to be widely conserved across phyla. However, except in a few described cases, rather little is known about their endogenous target genes and the physiological pathways they impinge on. Invertebrate model organisms such as C. elegans and Drosophila have been instrumental to develop methods and to dissect biological roles of miRNAs. In this review, we will focus on recent progress in characterizing miRNAs and steps toward identification of target genes in Drosophila. Many of these recent experiments provide evidence that a systematic target discovery is feasible and that the biology of miRNAs can be functionally explored using forward and reverse genetic tools.
- Published
- 2004
23. Sticking Around: Short-Range Activity of Wnt Ligands
- Author
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Christof Niehrs and Michael Boutros
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0301 basic medicine ,Male ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell membrane ,Wnt3 Protein ,03 medical and health sciences ,Intestinal mucosa ,medicine ,Animals ,Intestinal Mucosa ,Stem Cell Niche ,Molecular Biology ,Wnt Signaling Pathway ,Stem Cells ,Cell Membrane ,Wnt signaling pathway ,LRP6 ,LRP5 ,Cell Biology ,Short distance ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Female ,Stem cell ,Homeostasis ,Developmental Biology - Abstract
Wnt ligands are secreted lipid-modified proteins that are essential for development and homeostasis. Published recently in Nature, Farin et al. (2016) report that Wnt3 acts at a short distance during growth of mouse intestinal organoids, suggesting that Wnt proteins remain membrane-bound to activate signaling at a short range from their source.
- Published
- 2016
- Full Text
- View/download PDF
24. Signaling Role of Hemocytes in Drosophila JAK/STAT-Dependent Response to Septic Injury
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Ulla Maja Petersen, Hervé Agaisse, Michael Boutros, Norbert Perrimon, Bernard Mathey-Prevot, Unité de recherche Génétique Microbienne (UGM), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
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Male ,Hemocytes ,Time Factors ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Fat Body ,Hemocyte differentiation ,0302 clinical medicine ,Sequence Analysis, Protein ,Adipocytes ,Drosophila Proteins ,Transgenes ,Cloning, Molecular ,Receptor ,In Situ Hybridization ,Regulation of gene expression ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Acute-phase protein ,Gene Expression Regulation, Developmental ,JAK-STAT signaling pathway ,Protein-Tyrosine Kinases ,Immunohistochemistry ,Cell biology ,[SDV] Life Sciences [q-bio] ,DNA-Binding Proteins ,INSECTE ,Cytokine ,Insect Proteins ,Drosophila ,Female ,Signal Transduction ,Bridged-Ring Compounds ,Transgene ,Biology ,Infections ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,medicine ,Animals ,RNA, Messenger ,Molecular Biology ,030304 developmental biology ,Membrane Proteins ,Receptors, Interleukin ,Cell Biology ,Blotting, Northern ,Immunology ,Trans-Activators ,030217 neurology & neurosurgery ,Transcription Factors ,Developmental Biology - Abstract
To characterize the features of JAK/STAT signaling in Drosophila immune response, we have identified totA as a gene that is regulated by the JAK/STAT pathway in response to septic injury. We show that septic injury triggers the hemocyte-specific expression of upd3, a gene encoding a novel Upd-like cytokine that is necessary for the JAK/STAT-dependent activation of totA in the Drosophila counterpart of the mammalian liver, the fat body. In addition, we demonstrate that totA activation also requires the NF-KB-like Relish pathway, indicating that fat body cells integrate the activity of NF-KB and JAK/STAT signaling pathways upon immune response. This study reveals that, in addition to the pattern recognition receptor-mediated NF-KB-dependent immune response, Drosophila undergoes a complex systemic response that is mediated by the production of cytokines in blood cells, a process that is similar to the acute phase response in mammals.
- Published
- 2003
25. Dishevelled Activates JNK and Discriminates between JNK Pathways in Planar Polarity and wingless Signaling
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Michael Boutros, Marek Mlodzik, Nuria Paricio, and David Strutt
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Ommatidial rotation ,Frizzled ,animal structures ,Molecular Sequence Data ,Dishevelled Proteins ,Wnt1 Protein ,Biology ,Eye ,General Biochemistry, Genetics and Molecular Biology ,Receptors, G-Protein-Coupled ,Proto-Oncogene Proteins ,AXIN1 ,Animals ,Drosophila Proteins ,Point Mutation ,Amino Acid Sequence ,Phosphorylation ,Adaptor Proteins, Signal Transducing ,Body Patterning ,Genetics ,chemistry.chemical_classification ,Models, Genetic ,Sequence Homology, Amino Acid ,Biochemistry, Genetics and Molecular Biology(all) ,JNK Mitogen-Activated Protein Kinases ,Wnt signaling pathway ,Membrane Proteins ,Signal transducing adaptor protein ,Phosphoproteins ,Frizzled Receptors ,Cell biology ,Dishevelled ,chemistry ,Calcium-Calmodulin-Dependent Protein Kinases ,DEP domain ,Insect Proteins ,Drosophila ,Mitogen-Activated Protein Kinases ,Signal transduction ,Signal Transduction - Abstract
Frizzled family proteins have been described as receptors of Wnt signaling molecules. In Drosophila, the two known Frizzled proteins are associated with distinct developmental processes. Genesis of epithelial planar polarity requires Frizzled, whereas Dfz2 affects morphogenesis by wingless-mediated signaling. Dishevelled is required in both signaling pathways. Here, we use genetic and overexpression assays to show that Dishevelled activates JNK cascades. Rescue analysis reveals different protein domain requirements in Dishevelled for the two pathways; the C-terminal DEP domain is essential to rescue planar polarity defects and induce JNK signaling. Furthermore, the planar polarity–specific dsh1 allele is mutated in the DEP domain. Our results indicate that different Wnt/Fz signals activate distinct intracellular pathways, and Dishevelled discriminates among them by distinct domain interactions.
- Published
- 1998
26. REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons
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Michael Boutros, Sandra Kim, Gail Mandel, José Tapia-Ramírez, Michael A. Frohman, Yelena M. Altshuller, Yingcong Zheng, Juan José Toledo-Aral, Jayhong A. Chong, and Susan D. Kraner
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Cell type ,Molecular Sequence Data ,Saccharomyces cerevisiae ,RE1-silencing transcription factor ,Biology ,Nervous System ,Sodium Channels ,General Biochemistry, Genetics and Molecular Biology ,Embryonic and Fetal Development ,Mice ,SCN3A ,Complementary DNA ,Animals ,Gene silencing ,Amino Acid Sequence ,Cloning, Molecular ,Transcription factor ,In Situ Hybridization ,Cell Nucleus ,Neurons ,Reporter gene ,Sequence Homology, Amino Acid ,Biochemistry, Genetics and Molecular Biology(all) ,Cell Differentiation ,Zinc Fingers ,Molecular biology ,Recombinant Proteins ,Repressor Proteins ,RCOR1 ,Gene Expression Regulation ,Organ Specificity ,biology.protein ,Transcription Factors - Abstract
Expression of the type II voltage-dependent sodium channel gene is restricted to neurons by a silencer element active in nonneuronal cells. We have cloned cDNA coding for a transcription factor (REST) that binds to this silencer element. Expression of a recombinant REST protein confers the ability to silence type II reporter genes in neuronal cell types lacking the native REST protein, whereas expression of a dominant negative form of REST in nonneuronal cells relieves silencing mediated by the native protein. REST transcripts in developing mouse embryos are detected ubiquitously outside of the nervous system. We propose that expression of the type II sodium channel gene in neurons reflects a default pathway that is blocked in nonneuronal cells by the presence of REST.
- Published
- 1995
27. 812: Systematic investigation of drug resistance factors in colorectal cancer cells using pooled CRISPR/Cas9 knockout screens
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S. Leible, T. Zhan, Michael Boutros, Marco Breinig, F. Heigwer, and MP Ebert
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Genetics ,Cancer Research ,Oncology ,Colorectal cancer ,medicine ,CRISPR ,Drug resistance ,Biology ,medicine.disease - Published
- 2014
28. 19-P001 Smed-evi/wntless is required for β-catenin-dependent and -independent processes during planarian regeneration
- Author
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Kerstin Bartscherer, Michael Boutros, Emili Saló, and Teresa Adell
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Embryology ,biology ,Planarian ,Regeneration (biology) ,Catenin ,biology.organism_classification ,Cell biology ,Developmental Biology - Published
- 2009
- Full Text
- View/download PDF
29. Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNA interference screen
- Author
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Alexandra Sapetschnig, Imme Krüger, Bastian Stielow, Guntram Suske, and Michael Boutros
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RNA-induced transcriptional silencing ,RNA interference ,Transcriptional repression ,Identification (biology) ,Biology ,Genome ,Cell biology ,Chromatin - Published
- 2008
30. Wnt secretion requires Evi, a conserved transmembrane protein
- Author
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Michael Boutros, Nadège Pelte, Kerstin Bartscherer, and Dierk Ingelfinger
- Subjects
L1 ,Chemistry ,CD69 ,Wnt secretion ,Transmembrane protein ,Cell biology - Published
- 2007
31. 85 Wnt secretion is required to maintain Wnt activity in colon cancer
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Michael Boutros, R. Spang, C.R. Ball, Oksana Voloshanenko, I. Augustin, Gerrit Erdmann, M. Metzig, T.D. Dubash, and Hanno Glimm
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Cancer Research ,Oncology ,Colorectal cancer ,Cancer research ,medicine ,Wnt signaling pathway ,LRP6 ,LRP5 ,Biology ,medicine.disease ,Wnt secretion - Published
- 2014
32. 842: Systematic phenotypic profiling of chemical-genetic interactions in human cancer cells
- Author
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Michael Boutros, Wolfgang Huber, Felix A. Klein, and Marco Breinig
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Cancer Research ,Oncology ,Profiling (information science) ,Computational biology ,Biology ,Phenotype ,Human cancer - Published
- 2014
33. [Untitled]
- Author
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Xavier Saelens, K. De Bosscher, Jan Tavernier, Koen Vercauteren, Sven Eyckerman, Philip Meuleman, Laura Icardi, Viola Gesellchen, Raffaele Mori, Michael Boutros, and Judith Verhelst
- Subjects
biology ,Immunology ,Hematology ,Biochemistry ,stat ,STAT protein ,biology.protein ,Cancer research ,Immunology and Allergy ,Protein inhibitor of activated STAT ,STAT1 ,STAT2 ,STAT3 ,Molecular Biology ,STAT4 ,STAT6 - Abstract
The activity of Signal Transducer and Activator of Transcription (STAT) proteins is regulated by a multitude of posttranslational modifications, which control different aspects of signal transduction. In particular, lysine acetylation and deacetylation has emerged as a critical modification, regulating the activity of all seven STAT members. Unlike tyrosine phosphorylation/dephosphorylation, which mainly acts as an on/off switch of STAT activity, the control exerted by acetylation appears multifaceted and by far more complex, exerting distinct and even opposed regulation to different STAT members. We observed that type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide siRNA screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as a novel regulator of STAT activity. Sin3a directly interacts with STAT3 and controls its acetylation status, its nuclear accumulation and DNA binding, strongly influencing the transcription of a subset of STAT3-responsive genes. Interfering with Sin3a expression restores, at least partially, the STAT3 transcriptional blockade observed upon IFN treatment. Strikingly, Sin3a exerts opposed regulation on ISGF3 activity, as it is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. We conclude that Sin3a contributes to the regulation of the balance between the activities of different STAT members, and interfering with its activity or expression may re-direct cytokine signals, favoring the onset of pathological conditions, such as autoimmune syndromes, inflammation and cancer.
- Published
- 2013
34. P131 STAT transcriptional activity is controlled by regulated deacetylation
- Author
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Sven Eyckerman, Xavier Saelens, Raffaele Mori, Philip Meuleman, Michael Boutros, Laura Icardi, Viola Gesellchen, Jan Tavernier, Koen Vercauteren, K. De Bosscher, and Judith Verhelst
- Subjects
biology ,YY1 ,Immunology ,Repressor ,Hematology ,Biochemistry ,Molecular biology ,Terminator (genetics) ,Transcriptional repressor complex ,biology.protein ,Immunology and Allergy ,SIN3A ,STAT1 ,STAT2 ,STAT3 ,Molecular Biology - Abstract
Introduction Tyrosine phosphorylation is a hallmark for activation of Signal Transducer and Activator of Transcription (STAT) proteins, but their transcriptional activity also depends on other secondary modifications. Type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Methods Simultaneous treatment with IFNa2 and Trichostatin A, as well as combined HDAC1/HDAC2 silencing, restores STAT3-dependent reporter gene and endogenous genes expression, strongly suggesting that HDAC1 and HDAC2 are directly involved in repressing IFNa-activated STAT3. We used the IFN-dependent STAT3 transcriptional blockade as read-out for a genome-wide RNAi repressor screen. Results Quite significantly, we identified multiple partners of the Sin3a/HDAC transcriptional repressor complex as negative regulators of STAT3 transcriptional activity, regardless to the STAT3 activating stimulus. Sin3a directly interacts with STAT3 and controls its acetylation status, its nuclear accumulation and DNA binding, strongly influencing the transcription of a subset of STAT3-responsive genes. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. Conclusion The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.
- Published
- 2012
35. CS16-4. STAT3 transcriptional activity is controlled by regulated acetylation
- Author
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Viola Gesellchen, Sven Eyckerman, Raffaele Mori, Michael Boutros, Karolien De Bosscher, Jan Tavernier, Sam Lievens, Laura Icardi, and Jennyfer Bultinck
- Subjects
Transcriptional activity ,biology ,Acetylation ,Immunology ,biology.protein ,Immunology and Allergy ,Hematology ,STAT3 ,Molecular Biology ,Biochemistry ,Cell biology - Published
- 2011
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