Position Effect on FGF13 Associated with X-Linked Congenital Generalized Hypertrichosis
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ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are The
0031-3998/07/6103-0267 PEDIATRIC RESEARCH Vol. 61, No. 3, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are the Predominant FGF Ligands Expressed in Human Fetal Growth Plate Cartilage PAVEL KREJCI, DEBORAH KRAKOW, PERTCHOUI B. MEKIKIAN, AND WILLIAM R. WILCOX Medical Genetics Institute [P.K., D.K., P.B.M., W.R.W.], Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Obstetrics and Gynecology [D.K.] and Department of Pediatrics [W.R.W.], UCLA School of Medicine, Los Angeles, California 90095 ABSTRACT: Fibroblast growth factors (FGF) regulate bone growth, (G380R) or TD (K650E) mutations (4–6). When expressed at but their expression in human cartilage is unclear. Here, we deter- physiologic levels, FGFR3-G380R required, like its wild-type mined the expression of entire FGF family in human fetal growth counterpart, ligand for activation (7). Similarly, in vitro cul- plate cartilage. Using reverse transcriptase PCR, the transcripts for tivated human TD chondrocytes as well as chondrocytes FGF1, 2, 5, 8–14, 16–19, and 21 were found. However, only FGF1, isolated from Fgfr3-K644M mice had an identical time course 2, 17, and 19 were detectable at the protein level. By immunohisto- of Fgfr3 activation compared with wild-type chondrocytes and chemistry, FGF17 and 19 were uniformly expressed within the showed no receptor activation in the absence of ligand (8,9). growth plate. In contrast, FGF1 was found only in proliferating and hypertrophic chondrocytes whereas FGF2 localized predominantly to Despite the importance of the FGF ligand for activation of the resting and proliferating cartilage. -
Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. -
Pathophysiological Roles of FGF Signaling in the Heart
MINI REVIEW ARTICLE published: 06 September 2013 doi: 10.3389/fphys.2013.00247 Pathophysiological roles of FGF signaling in the heart Nobuyuki Itoh* and Hiroya Ohta Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan Edited by: Cardiac remodeling progresses to heart failure, which represents a major cause of Marcel van der Heyden, University morbidity and mortality. Cardiomyokines, cardiac secreted proteins, may play roles Medical Center, Netherlands in cardiac remodeling. Fibroblast growth factors (FGFs) are secreted proteins with Reviewed by: diverse functions, mainly in development and metabolism. However, some FGFs play Marcel van der Heyden, University Medical Center, Netherlands pathophysiological roles in cardiac remodeling as cardiomyokines. FGF2 promotes cardiac Christian Faul, University of Miami hypertrophy and fibrosis by activating MAPK signaling through the activation of FGF Miller School of Medicine, USA receptor (FGFR) 1c. In contrast, FGF16 may prevent these by competing with FGF2 for the *Correspondence: binding site of FGFR1c. FGF21 prevents cardiac hypertrophy by activating MAPK signaling Nobuyuki Itoh, Department of through the activation of FGFR1c with β-Klotho as a co-receptor. In contrast, FGF23 Genetic Biochemistry, Kyoto α University Graduate School of induces cardiac hypertrophy by activating calcineurin/NFAT signaling without Klotho. Pharmaceutical Sciences, These FGFs play crucial roles in cardiac remodeling via distinct action mechanisms. These Yoshida-Shimoadachi, Sakyo, findings provide new insights into the pathophysiological roles of FGFs in the heart and Kyoto 606-8501, Japan may provide potential therapeutic strategies for heart failure. e-mail: itohnobu@ pharm.kyoto-u.ac.jp Keywords: FGF, heart, hypertrophy, fibrosis, heart failure, cardiomyokine INTRODUCTION mice and humans, respectively. -
1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. -
Instability Restricts Signaling of Multiple Fibroblast Growth Factors
Cell. Mol. Life Sci. DOI 10.1007/s00018-015-1856-8 Cellular and Molecular Life Sciences RESEARCH ARTICLE Instability restricts signaling of multiple fibroblast growth factors Marcela Buchtova • Radka Chaloupkova • Malgorzata Zakrzewska • Iva Vesela • Petra Cela • Jana Barathova • Iva Gudernova • Renata Zajickova • Lukas Trantirek • Jorge Martin • Michal Kostas • Jacek Otlewski • Jiri Damborsky • Alois Kozubik • Antoni Wiedlocha • Pavel Krejci Received: 18 June 2014 / Revised: 7 February 2015 / Accepted: 9 February 2015 Ó Springer Basel 2015 Abstract Fibroblast growth factors (FGFs) deliver ex- failure to activate FGF receptor signal transduction over tracellular signals that govern many developmental and long periods of time, and influence specific cell behavior regenerative processes, but the mechanisms regulating FGF in vitro and in vivo. Stabilization via exogenous heparin signaling remain incompletely understood. Here, we ex- binding, introduction of stabilizing mutations or lowering plored the relationship between intrinsic stability of FGF the cell cultivation temperature rescues signaling of un- proteins and their biological activity for all 18 members of stable FGFs. Thus, the intrinsic ligand instability is an the FGF family. We report that FGF1, FGF3, FGF4, FGF6, important elementary level of regulation in the FGF sig- FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and naling system. FGF22 exist as unstable proteins, which are rapidly de- graded in cell cultivation media. Biological activity of Keywords Fibroblast growth factor Á FGF Á Unstable Á FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, Proteoglycan Á Regulation and FGF20 is limited by their instability, manifesting as Electronic supplementary material The online version of this article (doi:10.1007/s00018-015-1856-8) contains supplementary material, which is available to authorized users. -
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Published OnlineFirst January 12, 2016; DOI: 10.1158/0008-5472.CAN-15-1859 Cancer Tumor and Stem Cell Biology Research Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1a and HIF2a Desir ee Schonenberger€ 1, Sabine Harlander1,2, Michal Rajski1, Robert A. Jacobs1,2,3, Anne-Kristine Lundby1,2, Mojca Adlesic1, Tomas Hejhal1, Peter J. Wild4, Carsten Lundby1,2, and Ian J. Frew1,2 Abstract The von Hippel–Lindau (VHL) tumor suppressor gene is inac- chondrial abundance and oxidative capacity, glycogen accu- tivated in the majority of clear cell renal cell carcinomas (ccRCC), mulation, and acquisition of a clear cell phenotype in Vhl- but genetic ablation of Vhl alone in mouse models is insufficient deficient renal epithelial cells. HIF1a, but not HIF2a, induced to recapitulate human tumorigenesis. One function of pVHL is to Warburg-like metabolism characterized by increased glycoly- regulate the stability of the hypoxia-inducible factors (HIF), sis, decreased oxygen consumption, and decreased ATP pro- which become constitutively activated in the absence of pVHL. duction in mouse embryonic fibroblasts, providing insights In established ccRCC, HIF1a has been implicated as a renal tumor into the cellular changes potentially occurring in Vhl mutant suppressor, whereas HIF2a is considered an oncoprotein. In this renal cells before ccRCC formation. Importantly, deletion of study, we investigated the contributions of HIF1a and HIF2a to either Hif1a or Hif2a completely prevented the formation of ccRCC initiation in the context of Vhl deficiency. We found that renal cysts and tumors in Vhl/Trp53 mutant mice. These find- deleting Vhl plus Hif1a or Hif2a specifically in the renal ings argue that both HIF1a and HIF2a exert protumorigenic epithelium did not induce tumor formation. -
FGF Signaling Network in the Gastrointestinal Tract (Review)
163-168 1/6/06 16:12 Page 163 INTERNATIONAL JOURNAL OF ONCOLOGY 29: 163-168, 2006 163 FGF signaling network in the gastrointestinal tract (Review) MASUKO KATOH1 and MASARU KATOH2 1M&M Medical BioInformatics, Hongo 113-0033; 2Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo 104-0045, Japan Received March 29, 2006; Accepted May 2, 2006 Abstract. Fibroblast growth factor (FGF) signals are trans- Contents duced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS- 1. Introduction RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/ 2. FGF family GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS~ 3. Regulation of FGF signaling by WNT MAPK signaling cascade is implicated in cell growth and 4. FGF signaling network in the stomach differentiation, the PI3K~AKT signaling cascade in cell 5. FGF signaling network in the colon survival and cell fate determination, and the PI3K~aPKC 6. Clinical application of FGF signaling cascade in cell polarity control. FGF18, FGF20 and 7. Clinical application of FGF signaling inhibitors SPRY4 are potent targets of the canonical WNT signaling 8. Perspectives pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. 1. Introduction Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, Fibroblast growth factor (FGF) family proteins play key roles while recombinant FGF2 protein and FGF4 expression vector in growth and survival of stem cells during embryogenesis, are applicable for therapeutic angiogenesis. Helicobacter tissues regeneration, and carcinogenesis (1-4). -
Mir-17-92 Fine-Tunes MYC Expression and Function to Ensure
ARTICLE Received 31 Mar 2015 | Accepted 22 Sep 2015 | Published 10 Nov 2015 DOI: 10.1038/ncomms9725 OPEN miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth Marija Mihailovich1, Michael Bremang1, Valeria Spadotto1, Daniele Musiani1, Elena Vitale1, Gabriele Varano2,w, Federico Zambelli3, Francesco M. Mancuso1,w, David A. Cairns1,w, Giulio Pavesi3, Stefano Casola2 & Tiziana Bonaldi1 The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c- MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 30 UTR shortening at different stages of tumorigenesis. 1 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy. 2 Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Molecular Genetics in Neuroblastoma Prognosis
children Review Molecular Genetics in Neuroblastoma Prognosis Margherita Lerone 1, Marzia Ognibene 1 , Annalisa Pezzolo 2 , Giuseppe Martucciello 3,4 , Federico Zara 1,4, Martina Morini 5,*,† and Katia Mazzocco 6,† 1 Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] (M.L.); [email protected] (M.O.); [email protected] (F.Z.) 2 IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] 3 Department of Pediatric Surgery, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] 4 Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, University of Genova, 16132 Genova, Italy 5 Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy 6 Department of Pathology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-010-5636-2633 † Authors share senior authorship. Abstract: In recent years, much research has been carried out to identify the biological and genetic characteristics of the neuroblastoma (NB) tumor in order to precisely define the prognostic subgroups for improving treatment stratification. This review will describe the major genetic features and the recent scientific advances, focusing on their impact on diagnosis, prognosis, and therapeutic solutions in NB clinical management. Keywords: neuroblastoma; genetics; TRK; liquid biopsy; exosomes; telomere maintenance; hypoxia Citation: Lerone, M.; Ognibene, M.; Pezzolo, A.; Martucciello, G.; Zara, F.; 1. Introduction Morini, M.; Mazzocco, K. Molecular Genetics in Neuroblastoma Prognosis. Neuroblastoma (NB) is a pediatric heterogeneous disease with a median age of Children 2021, 8, 456. https:// 17 months at diagnosis, which can evolve with a benign course or fatal illness, with a doi.org/10.3390/children8060456 natural history ranging from a benign course to a terminal illness [1–3]. -
Β-Catenin Signaling Dynamics Regulate Cell Fate in Differentiating Neural Stem Cells
β-Catenin signaling dynamics regulate cell fate in differentiating neural stem cells Alyssa B. Rosenblooma, Marcin Tarczynski a, Nora Lama, Ravi S. Kaneb,1, Lukasz J. Bugaja,c,1, and David V. Schaffera,d,e,f,1 aDepartment of Bioengineering, University of California, Berkeley, CA 94720; bSchool of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332; cDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104; dDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720; eDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and fHelen Wills Neuroscience Institute, University of California, Berkeley, CA 94720 Edited by Randall T. Moon, University of Washington, Seattle, WA, and approved September 21, 2020 (received for review May 4, 2020) Stem cells undergo differentiation in complex and dynamic environ- of how signaling dynamics impact cellular function. Optogenetics ments wherein instructive signals fluctuate on various timescales. has recently emerged as a field in which light—which can readily Thus, cells must be equipped to properly respond to the timing of be varied in intensity, space, and time—is harnessed to precisely signals, for example, to distinguish sustained signaling from transient modulate cell-signaling pathways. In this approach, light-sensitive noise. However, how stem cells respond to dynamic variations in proteins are engineered to interface with specific signaling path- differentiation cues is not well characterized. Here, we use optoge- ways, and the subsequent introduction of such an optogenetic netic activation of β-catenin signaling to probe the dynamic responses construct into cells renders the signaling pathway responsive to of differentiating adult neural stem cells (NSCs). -
Supplementary Information
Supplementary information Supplemental Figure 1. No tissue contamination is confirmed by immunostaining of anti-MHC antibodies in the human-mouse heterogeneous recombination. A: The mesenchymally exclusive expression of human MHC in recombinant of mouse dental epithelium and human dental mesenchyme after subrenal culture for 4 weeks. B: The mesenchymally exclusive expression of mouse MHC in the recombinant of human dental epithelium and mouse dental mesenchyme after subrenal culture for 7 days. C: The epithelially exclusive expression of human MHC in the recombinant of human dental epithelium and mouse dental mesenchyme after subrenal culture for 7 days. hdm, human bell-stage dental mesenchyme; mam, mouse ameloblasts; mdm, E13.5 mouse dental mesenchyme; hde, human bell-stage dental epithelium. Scale bar = 50 μm. Supplemental Figure 2. Expression pattern of FGF1, FGF2, FGF15/19, and FGF18 in human tooth germs at the cap and bell stages. In situ hybridization shows the expression of FGF1 (A, B), FGF2 (C, D), FGF15/19 (E, F), and FGF18 (G, H) in human molar germs at the cap (A, C, E, G) and bell (B, D, F, H) stages. de, dental epithelium; dm, dental mesenchyme; ek, enamel knot; sr, stellate reticulum; iee, inner enamel epithelium. Scale bar = 50 μm. Supplemental Figure 3. Fgf8 is ectopically expressed in E13.5 molar germs of Wnt1-Cre;R26RFgf8 mice. Immunostaining of FGF8 in E13.5 wild-type (A) and mutant (B) molar germs. de, dental epithelium; dm, dental mesenchyme. Scale bar: 50 μm. Supplemental Table 1. Comparison of the expression pattern of FGF ligands between human and mouse tooth germ at the cap and bell stages.