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Results: 1 to 10 of 12

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Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cells.
Cigliola V, Ghila L, Thorel F, van Gurp L, Baronnier D, Oropeza D, Gupta S, Miyatsuka T, Kaneto H, Magnuson MA, Osipovich AB, Sander M, Wright CEV, Thomas MK, Furuyama K, Chera S, Herrera PL
(2018) Nat Cell Biol 20: 1267-1277
MeSH Terms: Animals, Cell Differentiation, Cell Plasticity, Cell Proliferation, Female, Glucagon-Secreting Cells, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mice, Transgenic, Signal Transduction, Smoothened Receptor
Show Abstract · Added November 6, 2018
The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.
2 Communities
2 Members
1 Resources
16 MeSH Terms
Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action.
Hempel JE, Cadar AG, Hong CC
(2016) Bioorg Med Chem Lett 26: 1947-53
MeSH Terms: Cyclic Nucleotide Phosphodiesterases, Type 4, Dose-Response Relationship, Drug, HEK293 Cells, Hedgehog Proteins, Humans, Molecular Structure, Phosphodiesterase 4 Inhibitors, Pyrimidinones, Repressor Proteins, Signal Transduction, Smoothened Receptor, Structure-Activity Relationship
Show Abstract · Added March 17, 2016
From a high content in vivo screen for modulators of developmental patterning in embryonic zebrafish, we previously identified eggmanone (EGM1, 3) as a Hedgehog (Hh) signaling inhibitor functioning downstream of Smoothened. Phenotypic optimization studies for in vitro probe development utilizing a Gli transcription-linked stable luciferase reporter cell line identified EGM1 analogs with improved potency and aqueous solubility. Mechanistic profiling of optimized analogs indicated two distinct scaffold clusters: PDE4 inhibitors able to inhibit downstream of Sufu, and PDE4-independent Hh inhibitors functioning between Smo and Sufu. Each class represents valuable in vitro probes for elucidating the complex mechanisms of Hh regulation.
Published by Elsevier Ltd.
1 Communities
1 Members
0 Resources
12 MeSH Terms
An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.
Williams CH, Hempel JE, Hao J, Frist AY, Williams MM, Fleming JT, Sulikowski GA, Cooper MK, Chiang C, Hong CC
(2015) Cell Rep 11: 43-50
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Hedgehog Proteins, Phosphodiesterase 4 Inhibitors, Pyrimidinones, Receptors, G-Protein-Coupled, Signal Transduction, Small Molecule Libraries, Smoothened Receptor, Thiophenes, Transcriptional Activation, Zebrafish, Zebrafish Proteins
Show Abstract · Added April 5, 2015
Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
3 Members
0 Resources
14 MeSH Terms
Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
Garcia I, Crowther AJ, Gama V, Miller CR, Miller CR, Deshmukh M, Gershon TR
(2013) Oncogene 32: 2304-14
MeSH Terms: Animals, Apoptosis, Cell Differentiation, Cell Movement, Cerebellar Neoplasms, Cerebellum, Down-Regulation, Medulloblastoma, Mice, Mice, Transgenic, Neurogenesis, Proto-Oncogene Proteins c-bcl-2, Receptors, G-Protein-Coupled, Smoothened Receptor, Stem Cells, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
0 Communities
1 Members
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16 MeSH Terms
Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity.
Ihrie RA, Shah JK, Harwell CC, Levine JH, Guinto CD, Lezameta M, Kriegstein AR, Alvarez-Buylla A
(2011) Neuron 71: 250-62
MeSH Terms: Age Factors, Animals, Calbindins, Cell Movement, Cerebral Ventricles, Choline O-Acetyltransferase, Cytarabine, Estrogen Antagonists, Gene Expression Regulation, Hedgehog Proteins, Immunosuppressive Agents, Kruppel-Like Transcription Factors, Luminescent Proteins, Mice, Mice, Transgenic, Neural Stem Cells, Neurons, Olfactory Bulb, RNA, Messenger, Receptors, G-Protein-Coupled, S100 Calcium Binding Protein G, Signal Transduction, Smoothened Receptor, Stilbamidines, Tamoxifen, Time Factors, Tyrosine 3-Monooxygenase, Zinc Finger Protein GLI1
Show Abstract · Added August 21, 2012
Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.
Copyright © 2011 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
28 MeSH Terms
Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate.
Williams C, Kim SH, Ni TT, Mitchell L, Ro H, Penn JS, Baldwin SH, Solnica-Krezel L, Zhong TP
(2010) Dev Biol 341: 196-204
MeSH Terms: Animals, Arteries, Embryo, Nonmammalian, Endothelial Cells, Hedgehog Proteins, Receptors, G-Protein-Coupled, Signal Transduction, Smoothened Receptor, Veins, Zebrafish, Zebrafish Proteins
Show Abstract · Added October 9, 2013
In vertebrate embryos, the dorsal aorta and the posterior cardinal vein form in the trunk to comprise the original circulatory loop. Previous studies implicate Hedgehog (Hh) signaling in the development of the dorsal aorta. However, the mechanism controlling specification of artery versus vein remains unclear. Here, we investigated the cell-autonomous mechanism of Hh signaling in angioblasts (endothelial progenitor cells) during arterial-venous specification utilizing zebrafish mutations in Smoothened (Smo), a G protein-coupled receptor essential for Hh signaling. smo mutants exhibit an absence of the dorsal aorta accompanied by a reciprocal expansion of the posterior cardinal vein. The increased number of venous cells is equivalent to the loss of arterial cells in embryos with loss of Smo function. Activation of Hh signaling expands the arterial cell population at the expense of venous cell fate. Time-lapse imaging reveals two sequential waves of migrating progenitor cells that contribute to the dorsal aorta and the posterior cardinal vein, respectively. Angioblasts deficient in Hh signaling fail to contribute to the arterial wave; instead, they all migrate medially as a single population to form the venous wave. Cell transplantation analyses demonstrate that Smo plays a cell-autonomous role in specifying angioblasts to become arterial cells, and Hh signaling-depleted angioblasts differentiate into venous cells instead. Collectively, these studies suggest that arterial endothelial cells are specified and formed via repressing venous cell fate at the lateral plate mesoderm by Hh signaling during vasculogenesis.
Copyright 2010 Elsevier Inc. All rights reserved.
1 Communities
3 Members
0 Resources
11 MeSH Terms
Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish.
Ju B, Spitsbergen J, Eden CJ, Taylor MR, Chen W
(2009) Mol Cancer 8: 40
MeSH Terms: Animals, Animals, Genetically Modified, Green Fluorescent Proteins, Hedgehog Proteins, Histocytochemistry, Humans, Neoplasms, Experimental, Patched Receptors, Patched-1 Receptor, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Smoothened Receptor, Zebrafish, Zebrafish Proteins
Show Abstract · Added April 24, 2014
The zebrafish has become an important model for cancer research. Several cancer models have been established by transgenic expression of human or mouse oncogenes in zebrafish. Since it is amenable to efficient transgenesis, zebrafish have immense potential to be used for studying interaction of oncogenes and pathways at the organismal level. Using the Gal4VP16-UAS binary transgenic expression approach, we established stable transgenic lines expressing an EGFP fusion protein of an activated zebrafish Smoothened (Smoa1-EGFP). Expression of the zebrafish Smoa1-EGFP itself did not lead to tumor formation either in founder fish or subsequent generations, however, co-expressing a constitutively active human AKT1 resulted in several tumor types, including spindle cell sarcoma, rhabdomyoma, ocular melanoma, astrocytoma, and myxoma. All tumor types showed GFP expression and increased Patched 1 levels, suggesting involvement of zebrafish Smoa1 in tumorigenesis. Immunofluorescence studies showed that tumors also expressed elevated levels of phosphorylated AKT, indicating activation of the PI3K-AKT pathway. These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish.
0 Communities
1 Members
0 Resources
16 MeSH Terms
A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis.
Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, Porter FD, Beachy PA
(2003) Nat Genet 33: 508-13
MeSH Terms: 3T3 Cells, Animals, Anticholesteremic Agents, Cells, Cultured, Chick Embryo, Cholesterol, Cyclodextrins, Dose-Response Relationship, Drug, Hedgehog Proteins, Humans, Lovastatin, Mice, Models, Biological, Precipitin Tests, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Signal Transduction, Smith-Lemli-Opitz Syndrome, Smoothened Receptor, Time Factors, Trans-Activators, Transfection
Show Abstract · Added March 5, 2014
Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
Chen JK, Taipale J, Cooper MK, Beachy PA
(2002) Genes Dev 16: 2743-8
MeSH Terms: 3T3 Cells, Animals, Antineoplastic Agents, Binding Sites, Endoplasmic Reticulum, Hedgehog Proteins, Mice, Protein Binding, Protein Conformation, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Signal Transduction, Smoothened Receptor, Teratogens, Trans-Activators, Veratrum Alkaloids
Show Abstract · Added March 5, 2014
The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo). Cyclopamine also can reverse the retention of partially misfolded Smo in the endoplasmic reticulum, presumably through binding-mediated effects on protein conformation. These observations reveal the mechanism of cyclopamine's teratogenic and antitumor activities and further suggest a role for small molecules in the physiological regulation of Smo.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Patched acts catalytically to suppress the activity of Smoothened.
Taipale J, Cooper MK, Maiti T, Beachy PA
(2002) Nature 418: 892-7
MeSH Terms: 3T3 Cells, Amino Acid Sequence, Animals, Catalysis, Gene Deletion, Hedgehog Proteins, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Models, Biological, Mutation, Missense, Patched Receptors, Patched-1 Receptor, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Signal Transduction, Smoothened Receptor, Syndrome, Trans-Activators, Transfection, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.
0 Communities
1 Members
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22 MeSH Terms