The Experts below are selected from a list of 11184 Experts worldwide ranked by ideXlab platform
Norbert Perrimon - One of the best experts on this subject based on the ideXlab platform.
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a drosophila model of oral peptide therapeutics for adult Intestinal Stem Cell tumors
Disease Models & Mechanisms, 2020Co-Authors: Anjali Bajpai, Norbert Perrimon, Taushif Ahmad Quazi, Hongwen Tang, Nishat Manzar, Virender Singh, Ashwani Kumar Thakur, Bushra AteeqAbstract:Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven Intestinal Stem Cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper.
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a drosophila model of oral peptide therapeutics for adult Intestinal Stem Cell tumors
bioRxiv, 2020Co-Authors: Anjali Bajpai, Norbert Perrimon, Taushif Ahmad Quazi, Hongwen Tang, Nishat Manzar, Virender Singh, Ashwani Kumar Thakur, Bushra AteeqAbstract:ABSTRACT The proto-oncogene YAP /Yki, a transcription co-factor of the Hippo pathway, has been linked to many cancers. YAP interacts with DNA-binding TEAD/Sd proteins to regulate expression of its transcriptional targets. Disruption of YAP-TEAD therefore offers a potential therapeutic strategy. The mammalian Vestigial Like (VGLL) protein, specifically its TONDU domain, has been shown to competitively inhibit YAP-TEAD interaction and a TONDU peptide can suppress YAP-induced cancer. As TONDU could potentially be developed into a therapeutic peptide for multiple cancers, we evaluated its efficacy in Yki-driven adult Intestinal Stem Cell (ISC) tumors in Drosophila. We show that oral uptake of the TONDU peptide is highly effective at inhibiting Yki-driven gut tumors by suppressing YAP-TEAD interaction. Comparative proteomics of early and late stage Yki-driven ISC tumors revealed enrichment of a number of proteins, including members of the integrin signaling pathway, such as Talin, Vinculin and Paxillin. These, in turn displayed a decrease in their levels in TONDU-peptide treated tumors. Further, we show that Sd binds to the regulatory region of integrin-coding gene, mew, which codes for αPS1, a key integrin of the ISCs. In support to a possible role of integrins in Yki-driven ISC tumors, we show that genetic downregulation of mew arrests Yki-driven ISC proliferation, reminiscent of the effects of TONDU peptide. Altogether, our findings present a novel platform for screening therapeutic peptides and provide insights into tumor suppression mechanisms. SIGNIFICANCE STATEMENT Discovering novel strategies to inhibit oncogene activity is a priority in cancer biology. As signaling pathways are widely conserved between mammals and Drosophila, these questions can be effectively addressed in this model organism. Here, we show that progression of Drosophila Intestinal Stem Cell (ISC) tumors induced by gain of an oncogenic form of the transcription co-factor Yki can be suppressed by feeding a peptide corresponding to the conserved TONDU domain of Vestigial (Vg), which blocks binding of Yki to the Sd transcription factor. Further, we show that down regulation of the integrin signaling pathway is causally linked to TONDU-peptide-mediated ISC tumor suppression. Our findings reveal that Drosophila can be successfully used to screen peptides for their therapeutic applications.
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an in vivo rnai screen uncovers the role of ador signaling and adenosine deaminase in controlling Intestinal Stem Cell activity
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Brian J Franklin, Norbert Perrimon, Hongwen Tang, Yannik Regimbalddumas, Justine Ramos, Justin A Bosch, Christians VillaltaAbstract:Metabolites are increasingly appreciated for their roles as signaling molecules. To dissect the roles of metabolites, it is essential to understand their signaling pathways and their enzymatic regulations. From an RNA interference (RNAi) screen for regulators of Intestinal Stem Cell (ISC) activity in the Drosophila midgut, we identified adenosine receptor (AdoR) as a top candidate gene required for ISC proliferation. We demonstrate that Ras/MAPK and Protein Kinase A (PKA) signaling act downstream of AdoR and that Ras/MAPK mediates the major effect of AdoR on ISC proliferation. ExtraCellular adenosine, the ligand for AdoR, is a small metabolite that can be released by various Cell types and degraded in the extraCellular space by secreted adenosine deaminase. Interestingly, down-regulation of adenosine deaminase-related growth factor A (Adgf-A) from enterocytes is necessary for extraCellular adenosine to activate AdoR and induce ISC overproliferation. As Adgf-A expression and its enzymatic activity decrease following tissue damage, our study provides important insights into how the enzymatic regulation of extraCellular adenosine levels under tissue-damage conditions facilitates ISC proliferation.
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mir 263a regulates enac to maintain osmotic and Intestinal Stem Cell homeostasis in drosophila
Developmental Cell, 2017Co-Authors: Kevin Kim, Norbert Perrimon, Ruei Jiun HungAbstract:Proper regulation of osmotic balance and response to tissue damage is crucial in maintaining Intestinal Stem Cell (ISC) homeostasis. We found that Drosophila miR-263a downregulates the expression of epithelial sodium channel (ENaC) subunits in enterocytes (ECs) to maintain osmotic and ISC homeostasis. In the absence of miR-263a, the intraluminal surface of the intestine displays dehydration-like phenotypes, Na+ levels are increased in ECs, stress pathways are activated in ECs, and ISCs overproliferate. Furthermore, miR-263a mutants have increased bacterial load and expression of antimicrobial peptides. Strikingly, these phenotypes are reminiscent of the pathophysiology of cystic fibrosis (CF) in which loss-of-function mutations in the chloride channel CF transmembrane conductance regulator can elevate the activity of ENaC, suggesting that Drosophila could be used as a model for CF. Finally, we provide evidence that overexpression of miR-183, the human ortholog of miR-263a, can also directly target the expressions of all three subunits of human ENaC.
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enteroendocrine Cells support Intestinal Stem Cell mediated homeostasis in drosophila
Cell Reports, 2014Co-Authors: Alla Amcheslavsky, Ivan Bragatto, Dominique Ferrandon, Qi Li, Norbert Perrimon, Wei Song, Tony Y IpAbstract:Summary Intestinal Stem Cells in the adult Drosophila midgut are regulated by growth factors produced from the surrounding niche Cells including enterocytes and visceral muscle. The role of the other major Cell type, the secretory enteroendocrine Cells, in regulating Intestinal Stem Cells remains unclear. We show here that newly eclosed scute loss-of-function mutant flies are completely devoid of enteroendocrine Cells. These enteroendocrine Cell-less flies have normal ingestion and fecundity but shorter lifespan. Moreover, in these newly eclosed mutant flies, the diet-stimulated midgut growth that depends on the insulin-like peptide 3 expression in the surrounding muscle is defective. The depletion of Tachykinin-producing enteroendocrine Cells or knockdown of Tachykinin leads to a similar although less severe phenotype. These results establish that enteroendocrine Cells serve as an important link between diet and visceral muscle expression of an insulin-like growth factor to stimulate Intestinal Stem Cell proliferation and tissue growth.
Ramesh A. Shivdasani - One of the best experts on this subject based on the ideXlab platform.
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Cellular and molecular architecture of the Intestinal Stem Cell niche
Nature cell biology, 2020Co-Authors: Neil Mccarthy, Judith Kraiczy, Ramesh A. ShivdasaniAbstract:Intestinal Stem and progenitor Cells replicate and differentiate in distinct compartments, influenced by Wnt, BMP, and other subepithelial cues. The Cellular sources of these signals were long obscure because Intestinal mesenchyme was insufficiently characterised. In this Review, we discuss how recent mRNA profiles of mouse and human Intestinal submucosa, coupled with fine-resolution microscopy and gene and Cell disruptions, reveal a coherent picture of an organised tissue carrying Cells with distinct molecular properties and functions. The Intestinal Stem Cell niche McCarthy, Kraiczy and Shivdasani review the Cellular and molecular organisation of the mammalian Intestinal Stem Cell niche and its functions.
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epigenetic regulation of Intestinal Stem Cell differentiation
American Journal of Physiology-gastrointestinal and Liver Physiology, 2020Co-Authors: Michael P. Verzi, Ramesh A. ShivdasaniAbstract:To fulfill the lifelong need to supply diverse epithelial Cells, Intestinal Stem Cells (ISCs) rely on executing accurate transcriptional programs. This review addresses the mechanisms that control those programs. Genes that define Cell behaviors and identities are regulated principally through thousands of dispersed enhancers, each individually <1 kb long and positioned from a few to hundreds of kilobases away from transcription start sites, upstream or downstream from coding genes or within introns. Wnt, Notch, and other epithelial control signals feed into these cis-regulatory DNA elements, which are also common loci of polymorphisms and mutations that confer disease risk. Cell-specific gene activity requires promoters to interact with the correct combination of signal-responsive enhancers. We review the current state of knowledge in ISCs regarding active enhancers, the nucleosome modifications that may enable appropriate and hinder inappropriate enhancer-promoter contacts, and the roles of lineage-restricted transcription factors.
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wnt secretion from epithelial Cells and subepithelial myofibroblasts is not required in the mouse Intestinal Stem Cell niche in vivo
Stem cell reports, 2014Co-Authors: Adrianna San K Roman, Ramesh A. Shivdasani, Chenura D Jayewickreme, Charles L MurtaughAbstract:Wnt signaling is a crucial aspect of the Intestinal Stem Cell niche required for crypt Cell proliferation and differentiation. Paneth Cells or subepithelial myofibroblasts are leading candidate sources of the required Wnt ligands, but this has not been tested in vivo. To abolish Wnt-ligand secretion, we used Porcupine (Porcn) conditional-null mice crossed to strains expressing inducible Cre recombinase in the epithelium, including Paneth Cells (Villin-CreERT2); in smooth muscle, including subepithelial myofibroblasts (Myh11-CreERT2); and simultaneously in both compartments. Elimination of Wnt secretion from any of these compartments did not disrupt tissue morphology, Cell proliferation, differentiation, or Wnt pathway activity. Thus, Wnt-ligand secretion from these Cell populations is dispensable for Intestinal homeostasis, revealing that a minor Cell type or significant and unexpected redundancy is responsible for physiologic Wnt signaling in vivo.
Bruce A. Edgar - One of the best experts on this subject based on the ideXlab platform.
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an sh3px1 dependent endocytosis autophagy network restrains Intestinal Stem Cell proliferation by counteracting egfr erk signaling
Developmental Cell, 2019Co-Authors: Peng Zhang, Andreana N Holowatyj, Taylor Roy, Stephen M Pronovost, Marco Marchetti, Hanbin Liu, Cornelia M Ulrich, Bruce A. EdgarAbstract:Summary The effect of intraCellular vesicle trafficking on Stem-Cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains Intestinal Stem Cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human Cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.
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niche appropriation by drosophila Intestinal Stem Cell tumours
Nature Cell Biology, 2015Co-Authors: Devanjali Dutta, Parthive H Patel, Bruce A. EdgarAbstract:Mutations that inhibit differentiation in Stem Cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila Intestinal Stem Cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress-dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the Stem Cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective Stem Cells may be a common mechanism of early tumorigenesis.
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Intestinal Stem Cell function in Drosophila and mice.
Current opinion in genetics & development, 2012Co-Authors: Huaqi Jiang, Bruce A. EdgarAbstract:Epithelial Cells of the digestive tracts of most animals are short-lived, and are constantly replenished by the progeny of long-lived, resident Intestinal Stem Cells. Proper regulation of Intestinal Stem Cell maintenance, proliferation and differentiation is critical for maintaining gut homeostasis. Here we review recent genetic studies of Stem Cell-mediated homeostatic growth in the Drosophila midgut and the mouse small intestine, highlighting similarities and differences in the mechanisms that control Stem Cell proliferation and differentiation.
Xinhua Lin - One of the best experts on this subject based on the ideXlab platform.
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drosophila perlecan regulates Intestinal Stem Cell activity via Cell matrix attachment
Stem cell reports, 2014Co-Authors: Jia You, Yan Zhang, Zhefeng Lou, Longjin Jin, Xinhua LinAbstract:Stem Cells require specialized local microenvironments, termed niches, for normal retention, proliferation, and multipotency. Niches are composed of Cells together with their associated extraCellular matrix (ECM). Currently, the roles of ECM in regulating niche functions are poorly understood. Here, we demonstrate that Perlecan (Pcan), a highly conserved ECM component, controls Intestinal Stem Cell (ISC) activities and ISC-ECM attachment in Drosophila adult posterior midgut. Loss of Pcan from ISCs, but not other surrounding Cells, causes ISCs to detach from underlying ECM, lose their identity, and fail to proliferate. These defects are not a result of a loss of epidermal growth factor receptor (EGFR) or Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity but partially depend on integrin signaling activity. We propose that Pcan secreted by ISCs confers niche properties to the adjacent ECM that is required for ISC maintenance of Stem Cell identity, activity, and anchorage to the niche.
Calvin J. Kuo - One of the best experts on this subject based on the ideXlab platform.
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the Intestinal Stem Cell niche homeostasis and adaptations
Trends in Cell Biology, 2018Co-Authors: Antonio J M Santos, Amanda T Mah, Calvin J. KuoAbstract:The Intestinal epithelium is a rapidly renewing Cellular compartment. This constant regeneration is a hallmark of Intestinal homeostasis and requires a tightly regulated balance between Intestinal Stem Cell (ISC) proliferation and differentiation. Since Intestinal epithelial Cells directly contact pathogenic environmental factors that continuously challenge their integrity, ISCs must also actively divide to facilitate regeneration and repair. Understanding niche adaptations that maintain ISC activity during homeostatic renewal and injury-induced Intestinal regeneration is therefore a major and ongoing focus for Stem Cell biology. Here, we review recent concepts and propose an active interconversion of the ISC niche between homeostasis and injury-adaptive states that is superimposed upon an equally dynamic equilibrium between active and reserve ISC populations.
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Ascl2 reinforces Intestinal Stem Cell identity.
Cell stem cell, 2015Co-Authors: Kelley S. Yan, Calvin J. KuoAbstract:Ascl2 is a Wnt-responsive master transcription factor that controls the Lgr5+ Intestinal Stem Cell gene expression program. Now in Cell Stem Cell, Schuijers et al. (2015) report an Ascl2 positive feedback loop, tuned by previous Wnt pathway activity, that perpetuates Intestinal Stem Cell identity in response to Wnt/R-spondin stimulation.
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The Intestinal Stem Cell.
Progress in molecular biology and translational science, 2010Co-Authors: Luis A. Chia, Calvin J. KuoAbstract:The Intestinal epithelium is one of the most rapidly proliferating organs in the body. A complete turnover of the epithelium occurs every 3-5 days in the mouse, a process that is maintained by a small population of Intestinal Stem Cells (ISCs) that reside in the crypt bases. The signals that regulate the behavior of these ISCs are still unknown. This has been due, until recently, to the singular lack of definitive ISC markers. The recent identification of genes that mark functional Stem Cells has yielded insights into how ISCs are regulated and maintained by their surrounding niche. Herein, we examine the body of literature regarding the precise identity and location of the ISCs, the role of the surrounding niche in ISC maintenance and regulation, as well as the hypothesis that the ISCs are the Cells of origin in colorectal cancer.
