DOCSLIB.ORG

Hippo-Foxa2 Signaling Pathway Plays a Role in Peripheral Lung Maturation and Surfactant Homeostasis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hippo-Foxa2 Signaling Pathway Plays a Role in Peripheral Lung Maturation and Surfactant Homeostasis Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis Chaeuk Chunga,b,c, Tackhoon Kimb, Miju Kimb, Minchul Kimb, Hoogeun Songb, Tae-Shin Kimb, Eunjeong Seob, Sang-Hee Leea, Hanbyul Kima,b, Sang Kyum Kima,b, Geon Yood, Da-Hye Leeb, Deog-Su Hwangd, Tatsuo Kinashie, Jin-Man Kimf, and Dae-Sik Limb,1 bDepartment of Biological Sciences, National Creative Research Initiatives Center, Biomedical Research Center, aGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; cDepartment of Pulmonary and Critical Care Medicine, and fDepartment of Pathology, Chungnam National University School of Medicine, Daejeon 301-721, Korea; dDepartment of Biological Sciences, Seoul National University, Seoul 151-742, Korea; and eDepartment of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka 570-8506, Japan Edited by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 1, 2013 (received for review November 27, 2012) Respiratory distress syndrome (RDS), which is induced by insufficient be involved in surfactant production and homeostasis during late production of surfactant, is the leading cause of mortality in preterm gestation (1, 4–7). Mice containing a mutation of TTF-1 or a de- babies. Although several transcription factors are known to be letion of Foxa2 or C/EBPα display immature type II pneumocytes involved in surfactant protein expression, the molecular mechanisms and lack type I pneumocytes without an alteration in branching and signaling pathways upstream of these transcription factors have morphogenesis, resulting in RDS (8, 9). Foxa2, TTF-1, and C/EBPα remained elusive. Here, using mammalian Hippo kinases (Mst1/2, reciprocally interact to regulate transcriptional targets of surfac- mammalian sterile 20-like kinase 1/2) conditional knockout mice, we tant synthesis and peripheral lung maturation (5). Some upstream demonstrate that Mst1/2 kinases are critical for orchestration of regulators, such as Nfatc3 (nuclear factor of activated T cells, transcription factors involved in surfactant protein homeostasis and cytoplasmic 3) and protein kinase A were identified (10, 11), but prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium so far the mechanism regulating peripheral lung maturation and exhibited perinatal mortality with respiratory failure and their lungs surfactant homeostasis are poorly understood and complex. contained fewer type I pneumocytes and more immature type II Mammalian sterile 20-like kinase 1 and 2 (Mst1/2) are upstream BIOLOGY pneumocytes lacking microvilli, lamellar bodies, and surfactant pro- kinases involved in the Hippo pathway, the unique signaling path- DEVELOPMENTAL tein expression, pointing to peripheral lung immaturity and RDS. In way involved in organ development and cancer (12). Interestingly, contrast to previous findings of YAP (Yes-associated protein)-mediated Mst1/2- and 45kD WW domain protein (WW45)-knockout mice canonical Hippo signaling in the liver and intestine, loss of Mst1/2 show a tendency to accumulate undifferentiated progenitor cells kinases induced the defects in pneumocyte differentiation in- (13, 14). For example, liver-specificablationofMst1/2 causes an dependently of YAP hyperactivity. We instead found that Mst1/2 increase in the number of hepatocytes and facultative progenitor kinases stabilized and phosphorylated the transcription factor cells (oval cells) (15). Intestine-specific ablation of Mst1/2 also Foxa2 (forkhead box A2), which regulates pneumocyte maturation results in intestinal progenitor cell proliferation and subsequent and surfactant protein expression. Taken together, our results colonic tumorigenesis (16, 17). The phenotypes of these organs suggest that the mammalian Hippo kinases play crucial roles in are attributed to hyperactivity of Yes-associated protein (YAP), surfactant homeostasis and coordination of peripheral lung differ- an oncogenic downstream effector molecule of the Hippo path- entiation through regulation of Foxa2 rather than of YAP. way. These studies suggest the interesting possibility that Yap- mediated Hippo signaling pathway, the so-called canonical Hippo non-canonical Hippo pathway | lung development pathway, works as critical inhibitor of epithelial progenitor cell proliferation in epithelial organs. Whether this paradigm is ap- eripheral lung immaturity and deficiency of pulmonary sur- plicable to other epithelial organs is not yet clear. Recent studies Pfactant cause many intractable pulmonary diseases. Deficit of have also demonstrated the role of Mst1/2 kinases in a YAP- surfactant because of preterm birth or genetic disorders of surfac- independent mechanism, the so-called noncanonical Hippo path- tant homeostasis induce respiratory distress syndrome (RDS) in the way. For example, Mst1 suppresses lymphoma development by newborn period (1). Dysregulation of these genes also underlies the promoting faithful chromosome segregation, independently of pathogenesis of many chronic lung diseases that have been con- YAP (18). Mst1/2 kinases also execute a variety of functions with sidered idiopathic, such as interstitial lung disease, pulmonary al- multiple partners, such as Foxo1, Foxo3, Akt, and Aurora B, in veolar proteinosis, and others (2). Elucidating the mechanism different biological contexts (19–22). underlying regulation of surfactant would be very helpful for un- We have now generated conditional double-knockout mice derstanding the molecular basis of refractory lung diseases of both (dKO) in which Mst1 and Mst2 were deleted in the developing lung infants and adults. epithelium. Our results revealed that Mst1/2 acts through modu- Alveoli are composed of type I and type II pneumocytes. The type lation of Foxa2 to play a critical role in the regulation of peripheral II pneumocyte is the progenitor cell of the type I pneumocyte and lung maturation and surfactant homeostasis with use of these mice. plays a central role in physiological pulmonary functions, especially surfactant production (3). Type I pneumocytes contact alveolar capillaries and participate in gas exchange. Lung morphogenesis in Author contributions: C.C., T. Kim, Minchul Kim, H.S., T.-S.K., E.S., and D.-S.L. designed research; C.C., Miju Kim, H.S., T.-S.K., H.K., and D.-H.L. performed research; D.S.H., mice is a dynamic process that can be divided into embryonic T. Kinashi, and J.-M.K. contributed new reagents/analytic tools; C.C., T. Kim, Minchul [embryonic day (E) 9–11.5], pseudoglandular (E11.5–16.5), cana- Kim, E.S., S.-H.L., S.K.K., and J.-M.K. analyzed data; and C.C., T. Kim, G.Y., and D.-S.L. licular (E16.5–17.5), saccular [E17.5 to postnatal (PN) day 5], and wrote the paper. alveolar (PN5–28) stages. During canalicular and saccular stages in The authors declare no conflict of interest. late gestation, peripheral lungs containing type I and II pneumo- This article is a PNAS Direct Submission. cytes fully differentiate in preparation for postnatal respiration (4). Freely available online through the PNAS open access option. Many transcription factors, including Foxa2 (forkhead box A2), 1To whom correspondence should be addressed. E-mail: [email protected]. TTF-1 (thyroid transcription factor-1)/Nkx2.1 (NK2 homeobox 1), This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and C/EBPα (CCAAT/enhancer binding protein-α), are known to 1073/pnas.1220603110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1220603110 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 Results emphysematous lesions (Fig. 1C and Fig. S3A), suggesting the Lung-Specific Mst1/2-dKO Mice Succumb to RDS and Die in the Mst1/2-dKO mice died because of respiratory failure. Perinatal Period. Mst1/2-null mice lacking both Mst1 and Mst2 We then determined the onset of aberrant phenotype from E15.5 genes begin dying in utero at embryonic day 8.5 because of defects to E18.5. Until E17.5, there were no significant differences between in placental development and yolk sac/embryonic vascular pat- the lungs of Mst1/2-dKO mice and control mice (Fig. 1B). At that terning (21). To investigate the role of Mst1/2 in lung development, time, embryonic markers such as Sox9 (sex-determining region Y fl fl − − we crossed Mst1 / ;Mst2 / mice with Nkx2.1-Cre mice to generate box 9, a marker for distal lung progenitor cells) and Sox2 (marker fl fl − − the lung-specific Mst1/2-knockout mouse, Mst1 / ;Mst2 / ;Nkx2.1- for proximal lung progenitor cells) were also normally expressed in − − Cre, hereafter termed Mst1/2-dKO. Mst2 / mice did not show any Mst1/2 dKO lungs (23) (Fig.1D,andFig. S4 A and B). However, noticeable developmental or immunological defects (15). We alveoli of Mst1/2-dKO lungs at E18.5 and PN1 showed a re- confirmed the efficient deletion of Mst1 in the Mst2-null lung tis- markably reduced aerated space compacted with immature-looking sues (Fig. S1 A and B). LacZ staining showed that Nkx2.1 Cre was cuboidal cells (Fig. 1 B and C). At around PN5, Mst1/2-dKO lungs expressed in lung epithelial cells (Fig. S1C). Mst1/2-dKO mice were displayed spontaneous infiltration of inflammatory cells and hya- born at normal Mendelian ratio. Lung size and dry lung weight line membrane formation, which are characteristics typical of RDS were comparable between Mst1/2 dKO mice and control mice at in preterm infants (1), at which point the destruction of lung be- E15.5 and E18.5 (Fig. 1A and Fig. S2). However, Mst1/2-dKO mice came aggravated (Fig. 1C). No bacteria and fungi were detected in exhibited a markedly sick appearance at birth and almost all mice lung sections or in cytospins of bronchoalveolar lavage fluid, ruling died within the first 15 d after birth (Fig. S1D). At PN10, Mst1/ out the possibility of infection (Fig. 1C and Fig. S3B). 2-dKO lung showed severe accumulation of inflammatory cells We determined whether Mst1 and Mst2 affect cell proliferation in the alveolar space and bronchiole with multiple atelectasis and and apoptosis by performing BrdU labeling and TUNEL assays, fl fl − − Fig.
Load more

Recommended publications
  • Activated Peripheral-Blood-Derived Mononuclear Cells
    Transcription factor expression in lipopolysaccharide- activated peripheral-blood-derived mononuclear cells Jared C. Roach*†, Kelly D. Smith*‡, Katie L. Strobe*, Stephanie M. Nissen*, Christian D. Haudenschild§, Daixing Zhou§, Thomas J. Vasicek¶, G. A. Heldʈ, Gustavo A. Stolovitzkyʈ, Leroy E. Hood*†, and Alan Aderem* *Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103; ‡Department of Pathology, University of Washington, Seattle, WA 98195; §Illumina, 25861 Industrial Boulevard, Hayward, CA 94545; ¶Medtronic, 710 Medtronic Parkway, Minneapolis, MN 55432; and ʈIBM Computational Biology Center, P.O. Box 218, Yorktown Heights, NY 10598 Contributed by Leroy E. Hood, August 21, 2007 (sent for review January 7, 2007) Transcription factors play a key role in integrating and modulating system. In this model system, we activated peripheral-blood-derived biological information. In this study, we comprehensively measured mononuclear cells, which can be loosely termed ‘‘macrophages,’’ the changing abundances of mRNAs over a time course of activation with lipopolysaccharide (LPS). We focused on the precise mea- of human peripheral-blood-derived mononuclear cells (‘‘macro- surement of mRNA concentrations. There is currently no high- phages’’) with lipopolysaccharide. Global and dynamic analysis of throughput technology that can precisely and sensitively measure all transcription factors in response to a physiological stimulus has yet to mRNAs in a system, although such technologies are likely to be be achieved in a human system, and our efforts significantly available in the near future. To demonstrate the potential utility of advanced this goal. We used multiple global high-throughput tech- such technologies, and to motivate their development and encour- nologies for measuring mRNA levels, including massively parallel age their use, we produced data from a combination of two distinct signature sequencing and GeneChip microarrays.
    [Show full text]
  • View Is Portrayed Schematically in Figure 7B
    BASIC RESEARCH www.jasn.org Recombination Signal Binding Protein for Ig-kJ Region Regulates Juxtaglomerular Cell Phenotype by Activating the Myo-Endocrine Program and Suppressing Ectopic Gene Expression † † ‡ Ruth M. Castellanos-Rivera,* Ellen S. Pentz,* Eugene Lin,* Kenneth W. Gross, † Silvia Medrano,* Jing Yu,§ Maria Luisa S. Sequeira-Lopez,* and R. Ariel Gomez* *Department of Pediatrics, School of Medicine, †Department of Biology, Graduate School of Arts and Sciences, and §Department of Cell Biology, University of Virginia, Charlottesville, Virginia; and ‡Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York ABSTRACT Recombination signal binding protein for Ig-kJ region (RBP-J), the major downstream effector of Notch signaling, is necessary to maintain the number of renin-positive juxtaglomerular cells and the plasticity of arteriolar smooth muscle cells to re-express renin when homeostasis is threatened. We hypothesized that RBP-J controls a repertoire of genes that defines the phenotype of the renin cell. Mice bearing a bacterial artificial chromosome reporter with a mutated RBP-J binding site in the renin promoter had markedly reduced reporter expression at the basal state and in response to a homeostatic challenge. Mice with conditional deletion of RBP-J in renin cells had decreased expression of endocrine (renin and Akr1b7)and smooth muscle (Acta2, Myh11, Cnn1,andSmtn) genes and regulators of smooth muscle expression (miR- 145, SRF, Nfatc4, and Crip1). To determine whether RBP-J deletion decreased the endowment of renin cells, we traced the fate of these cells in RBP-J conditional deletion mice. Notably, the lineage staining patterns in mutant and control kidneys were identical, although mutant kidneys had fewer or no renin- expressing cells in the juxtaglomerular apparatus.
    [Show full text]
  • The Title of the Dissertation
    UNIVERSITY OF CALIFORNIA SAN DIEGO Novel network-based integrated analyses of multi-omics data reveal new insights into CD8+ T cell differentiation and mouse embryogenesis A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Kai Zhang Committee in charge: Professor Wei Wang, Chair Professor Pavel Arkadjevich Pevzner, Co-Chair Professor Vineet Bafna Professor Cornelis Murre Professor Bing Ren 2018 Copyright Kai Zhang, 2018 All rights reserved. The dissertation of Kai Zhang is approved, and it is accept- able in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California San Diego 2018 iii EPIGRAPH The only true wisdom is in knowing you know nothing. —Socrates iv TABLE OF CONTENTS Signature Page ....................................... iii Epigraph ........................................... iv Table of Contents ...................................... v List of Figures ........................................ viii List of Tables ........................................ ix Acknowledgements ..................................... x Vita ............................................. xi Abstract of the Dissertation ................................. xii Chapter 1 General introduction ............................ 1 1.1 The applications of graph theory in bioinformatics ......... 1 1.2 Leveraging graphs to conduct integrated analyses .......... 4 1.3 References .............................. 6 Chapter 2 Systematic
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The DNA Methylation of FOXO3 and TP53 As a Blood Biomarker of Late
    Yuan et al. J Transl Med (2020) 18:467 https://doi.org/10.1186/s12967-020-02643-y Journal of Translational Medicine RESEARCH Open Access The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma Lin Yuan1,2,3, Leyuan Wang2, Xizi Du2, Ling Qin1,3, Ming Yang4, Kai Zhou2, Mengping Wu2, Yu Yang2, Zhiyuan Zheng1,3, Yang Xiang2, Xiangping Qu2, Huijun Liu2, Xiaoqun Qin2 and Chi Liu1,2,5* Abstract Background: Late-onset asthma (LOA) is beginning to account for an increasing proportion of asthma patients, which is often underdiagnosed in the elderly. Studies on the possible relations between aging-related genes and LOA contribute to the diagnosis and treatment of LOA. Forkhead Box O3 (FOXO3) and TP53 are two classic aging-related genes. DNA methylation varies greatly with age which may play an important role in the pathogenesis of LOA. We supposed that the diferentially methylated sites of FOXO3 and TP53 associated with clinical phenotypes of LOA may be useful biomarkers for the early screening of LOA. Methods: The mRNA expression and DNA methylation of FOXO3 and TP53 in peripheral blood of 43 LOA patients (15 mild LOA, 15 moderate LOA and 13 severe LOA) and 60 healthy controls (HCs) were determined. The association of methylated sites with age was assessed by Cox regression to control the potential confounders. Then, the correlation between diferentially methylated sites (DMSs; p-value < 0.05) and clinical lung function in LOA patients was evalu- ated. Next, candidate DMSs combining with age were evaluated to predict LOA by receiver operating characteristic (ROC) analysis and principal components analysis (PCA).
    [Show full text]
  • Predictive Toxicogenomics for the Identification of Chemical Carcinogens : Application to Human Hepatic Cell Lines
    Predictive toxicogenomics for the identification of chemical carcinogens : application to human hepatic cell lines Citation for published version (APA): Christina Magkoufopoulou, C. (2011). Predictive toxicogenomics for the identification of chemical carcinogens : application to human hepatic cell lines. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20111208cc Document status and date: Published: 01/01/2011 DOI: 10.26481/dis.20111208cc Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.
    [Show full text]
  • The E–Id Protein Axis Modulates the Activities of the PI3K–AKT–Mtorc1
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1– Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis Masaki Miyazaki,1,8 Kazuko Miyazaki,1,8 Shuwen Chen,1 Vivek Chandra,1 Keisuke Wagatsuma,2 Yasutoshi Agata,2 Hans-Reimer Rodewald,3 Rintaro Saito,4 Aaron N. Chang,5 Nissi Varki,6 Hiroshi Kawamoto,7 and Cornelis Murre1 1Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; 2Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan; 3Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany; 4Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA; 5Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA; 6Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA; 7Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naı¨ve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells.
    [Show full text]
  • A Flexible Microfluidic System for Single-Cell Transcriptome Profiling
    www.nature.com/scientificreports OPEN A fexible microfuidic system for single‑cell transcriptome profling elucidates phased transcriptional regulators of cell cycle Karen Davey1,7, Daniel Wong2,7, Filip Konopacki2, Eugene Kwa1, Tony Ly3, Heike Fiegler2 & Christopher R. Sibley 1,4,5,6* Single cell transcriptome profling has emerged as a breakthrough technology for the high‑resolution understanding of complex cellular systems. Here we report a fexible, cost‑efective and user‑ friendly droplet‑based microfuidics system, called the Nadia Instrument, that can allow 3′ mRNA capture of ~ 50,000 single cells or individual nuclei in a single run. The precise pressure‑based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efciencies that compare favorably in the feld. Moreover, when combined with the Nadia Innovate, the system can be transformed into an adaptable setup that enables use of diferent bufers and barcoded bead confgurations to facilitate diverse applications. Finally, by 3′ mRNA profling asynchronous human and mouse cells at diferent phases of the cell cycle, we demonstrate the system’s ability to readily distinguish distinct cell populations and infer underlying transcriptional regulatory networks. Notably this provided supportive evidence for multiple transcription factors that had little or no known link to the cell cycle (e.g. DRAP1, ZKSCAN1 and CEBPZ). In summary, the Nadia platform represents a promising and fexible technology for future transcriptomic studies, and other related applications, at cell resolution. Single cell transcriptome profling has recently emerged as a breakthrough technology for understanding how cellular heterogeneity contributes to complex biological systems. Indeed, cultured cells, microorganisms, biopsies, blood and other tissues can be rapidly profled for quantifcation of gene expression at cell resolution.
    [Show full text]
  • 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
    [Show full text]
  • Regulation of PERK Expression by FOXO3: a Vulnerability of Drug- Resistant Cancer Cells
    Oncogene (2019) 38:6382–6398 https://doi.org/10.1038/s41388-019-0890-7 ARTICLE Regulation of PERK expression by FOXO3: a vulnerability of drug- resistant cancer cells 1 1 1 1 1 Glowi Alasiri ● Yannasittha Jiramongkol ● Stefania Zona ● Lavender Y. -N. Fan ● Zimam Mahmud ● 2 2 1 Gyungyub Gong ● Hee Jin Lee ● Eric W. -F. Lam Received: 15 February 2019 / Revised: 28 June 2019 / Accepted: 2 July 2019 / Published online: 16 July 2019 © The Author(s) 2019. This article is published with open access Abstract The major impediment to effective cancer therapy has been the development of drug resistance. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and mediates the cytotoxic and cytostatic functions of cancer therapeutics. In consequence, FOXO3 is often downregulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. Consistently, we find that FOXO3 expression is attenuated in the drug- resistant MCF-7-EpiR and MCF-7-TaxR compared to the parental MCF-7 breast cancer cells. Using ChIP, short-interfering RNA (siRNA) knockdown, and overexpression assays as well as Foxo1/3/4−/− MEFs, we establish the endoplasmic reticulum 1234567890();,: 1234567890();,: (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. In agreement, there is also a positive correlation between FOXO3 and PERK expression at the protein and RNA levels in breast cancer patient samples. We uncover that PERK expression is downregulated but its activity constitutively elevated in the drug- resistant cells. With this in mind, we exploit this adaptive response of low FOXO3 and PERK expression, and high PERK activity in drug-resistant breast cancer cells and show that these drug-resistant cells are specifically sensitive to PERK inhibition.
    [Show full text]
  • Genequery™ Human Stem Cell Transcription Factors Qpcr Array
    GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) Catalog #GK125 Product Description ScienCell's GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) surveys a panel of 88 transcription factors related to stem cell maintenance and differentiation. Transcription factors are proteins that can regulate target gene transcription level by binding to specific regions of the genome known as enhancers or silencers. Brief examples of how genes may be grouped according to their functions are shown below: • Pluripotency transcription factors: NANOG, POU5F1, SOX2 • Embryonic development: EOMES, FOXC2/D3/O1, HOXA9/A10, KLF2/5, LIN28B, MAX, PITX2, SMAD1, TBX5, ZIC1 • Germ layer formation and differentiation: FOXA2, GATA6, HAND1, ISL1, KLF4, SMAD2, SOX9 • Organ morphogenesis: EZH2, HOXA11/B3/B5/C9, MSX2, MYC, PAX5/8, VDR • Angiogenesis: CDX2, JUN, NR2F2, RUNX1, WT1 • Hematopoiesis and osteogenesis: EGR3, ESR1, GATA1/2/3, GLI2, NFATC1, PAX9, RB1, SOX6, SP1, STAT1 • Neural stem cell maintenance and differentiation: ATF2, CREB1, FOSB, FOXO3, HES1, HOXD10, MCM2/7, MEF2C, NEUROD1/G1, OLIG1/2, PAX3/6, POU4F1, PPARG, SMAD3/4, SNAI1, STAT3 Note : all gene names follow their official symbols by the Human Genome Organization Gene Nomenclature Committee (HGNC). GeneQuery™ qPCR array kits are qPCR ready in a 96-well plate format, with each well containing one primer set that can specifically recognize and efficiently amplify a target gene's cDNA. The carefully designed primers ensure that: (i) the optimal annealing temperature in qPCR analysis is 65°C (with 2 mM Mg 2+ , and no DMSO); (ii) the primer set recognizes all known transcript variants of target gene, unless otherwise indicated; and (iii) only one gene is amplified.
    [Show full text]
  • What Your Genome Doesn't Tell
    UC San Diego UC San Diego Electronic Theses and Dissertations Title Multi-layered epigenetic control of T cell fate decisions Permalink https://escholarship.org/uc/item/8rs7c7b3 Author Yu, Bingfei Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA SAN DIEGO Multi-layered epigenetic control of T cell fate decisions A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biology by Bingfei Yu Committee in charge: Professor Ananda Goldrath, Chair Professor John Chang Professor Stephen Hedrick Professor Cornelis Murre Professor Wei Wang 2018 Copyright Bingfei Yu, 2018 All rights reserved. The dissertation of Bingfei Yu is approved, and it is ac- ceptable in quality and form for publication on microfilm and electronically: Chair University of California San Diego 2018 iii DEDICATION To my parents who have been giving me countless love, trust and support to make me who I am. iv EPIGRAPH Stay hungary. Stay foolish. | Steve Jobs quoted from the back cover of the 1974 edition of the Whole Earth Catalog v TABLE OF CONTENTS Signature Page.................................. iii Dedication..................................... iv Epigraph.....................................v Table of Contents................................. vi List of Figures.................................. ix Acknowledgements................................x Vita........................................ xii Abstract of
    [Show full text]