DOCSLIB.ORG

Multilayer Control of the EMT Master Regulators

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Multilayer Control of the EMT Master Regulators Oncogene (2014) 33, 1755–1763 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Multilayer control of the EMT master regulators H Zheng and Y Kang Metastasis is the leading cause of cancer-associated death in most tumor types. Metastatic dissemination of cancer cells from the primary tumor is believed to be initiated by the reactivation of an embryonic development program referred to as epithelial– mesenchymal transition (EMT), whereby epithelial cells lose apicobasal polarity and cell–cell contacts, and gain mesenchymal phenotypes with increased migratory and invasive capabilities. EMT has also been implicated in the regulation of cancer stem cell property, immune suppression and cancer regression. Several transcription factors have been identified as master regulators of EMT, including the Snail, Zeb and Twist families, and their expression is tightly regulated at different steps of transcription, translation and protein stability control by a variety of cell-intrinsic pathways as well as extracellular cues. Here, we review the recent literature on the signaling pathways and mechanisms that control the expression of these master transcription factors during EMT and cancer progression. Oncogene (2014) 33, 1755–1763; doi:10.1038/onc.2013.128; published online 22 April 2013 Keywords: cancer metastasis; EMT; Snail; Twist; Zeb; E3-ubiquitin ligase EMT AND CANCER METASTASIS embryogenesis, EMT has a key role in the formation of various Ninety percent of cancer-related deaths are not caused by tissues and organs such as the neural crest, heart, musculoskeletal 7–9 the growth of primary tumors but rather by the spread of and peripheral nervous systems. In adult organisms, only a cancer cells to distant secondary organs.1–3 Despite its devastating certain subset of cells retains the ability to undergo EMT in specific consequence, cancer metastasis is in fact a very inefficient process physiological or pathological conditions, such as wound healing. that requires tumor cells to overcome a series of challenging However, during cancer progression, tumor cells often gain the hurdles as they spread from the primary tumor to secondary ability to reactivate the EMT program and use it for their own 12 organs.4,5 During the expansion of the primary tumor, benefits. Several in vitro cell culture models and mouse models accumulating genetic and epigenetic changes, as well as tumor of cancer progression have shown that reactivation of EMT by microenvironment cues, cause a small portion of tumor cells to tumor cells confers selective advantages, including enhanced disseminate from the tumor mass, invade through the basement motility and invasiveness during tumor progression that is membrane, escape the host immune surveillance, enter systemic believed to be pre-requisite for tumor cell dissemination and 7–9,13 circulation, and spread to secondary organs. Disseminated tumor metastasis. cells then extravasate through the capillary endothelium into surrounding tissues, find a way to survive in the new environment and eventually grow to become clinically detectable DYNAMICS OF EMT AND MESENCHYMAL-TO-EPITHELIAL macrometastases. TRANSITION IN METASTASIS As an early step in cancer metastasis, tumor cells need to gain In tumor biology, EMT has been extensively studied using in vitro their ability to disseminate from solid tumor mass and invade into cell line models, but direct observation of EMT in vivo, particularly the surrounding stromal tissues either as a group of cells (cohesive in clinical specimens, has been difficult and there has been migration) or as single cells (mesenchymal invasion or amoeboid skepticism regarding its pathological relevance.14,15 Analysis of invasion).6 As epithelial tumor cells are usually tightly associated clinical patient samples have demonstrated features of EMT with their neighboring cells via E-cadherin-containing adherens among cancer cells in the invasive front of a number of different junctions, tumor cells must break these intercellular junctions tumor types,16–19 but success in identifying EMT-transitioning cells before they can move out as single cells and invade stromal in vivo has been hampered by the spatial and temporal tissues. Epithelial tumor cells may undergo a process termed as heterogeneity of EMT in human cancer and lack of reliable EMT epithelial-to-mesenchymal transition (EMT) to facilitate this type of markers that can distinguish tumor cells having undergone EMT cellular invasion (Figure 1), which can be stimulated either by from surrounding stromal cells.20 One explanation for this is that extracellular cytokines, such as TGF-b, EGF, FGF, or by intracellular cancer cells only undergo a transient EMT, reverting back to the cues, such as oncogenic Ras or NFkB signaling.7–11 During EMT, epithelial state by mesenchymal-to-epithelial transition (MET) epithelial cells lose their epithelial polarity and cell–cell contacts once they have penetrated stromal tissue, which facilitates and gain mesenchymal phenotypes with increased migratory and colonization in the target organs.21 Indeed, recent experimental invasive capabilities. A hallmark of EMT is the functional loss of evidence showed that although EMT can increases tumor invasion E-cadherin, while additional cellular changes, such as reduced and cancer stem cell properties,22 tumor cells undergoing EMT are expression of epithelial markers cytokeratins and ZO-1, and the often growth arrested since many EMT-inducing transcriptional overexpression of mesenchymal markers N-cadherin, Vimentin factors can directly inhibit proliferation.16,23–27 Thus, tumor cells and Fibronectin, are also often observed. During metazoan must undergo MET to revert to the epithelial state to allow Department of Molecular Biology, Princeton University, Princeton, NJ, USA. Correspondence: Professor Y Kang, Department of Molecular Biology, Princeton University, LTL255, Washington Road, Princeton, NJ 08544, USA. E-mail: [email protected] Received 9 February 2013; revised 27 February 2013; accepted 27 February 2013; published online 22 April 2013 Multilayer control of the EMT master regulators H Zheng and Y Kang 1756 metastatic growth in distant organs. The mechanisms underlying cancer—perhaps the seeds of metastasis have disseminated years the induction of MET are largely unknown but it is suspected that before the clinical detection of primary pancreatic cancer. withdrawal of EMT inducers, resulting from changes in the stromal In aggregate, recent advances in clinical and experimental studies cues provided by the surrounding environment, is a potential have firmly established the pathological relevance of EMTs in cause of MET. In support of the sequential EMT/MET model, cancer metastasis and underscore the importance of elucidating dynamic expression of E-cadherin has been documented in cancer molecular mechanism that controls such transitions. progression.28 Whereas those cells that undergo hypermethylation and repression of CDH1 in primary breast cancers are more invasive and metastatic, subsequent TRANSCRIPTION FACTORS IN EMT demethylation and reactivation of CDH1 during the process of As a crucial ‘gate-keeper’ of epithelial characteristics, E-cadherin is metastasis is observed. Consistent with the dynamic expression of mutated or downregulated in many cancer types and is associated CDH1, it has been reported that E-cadherin levels are elevated in with increased invasive behavior of tumor cells.8 For example, in lymph-node metastases relative to matched primary tumor breast cancer, at least 6% of breast cancer patients’ genomes samples, suggesting once again that EMT in primary tumors is 37 29–31 harbor E-cadherin null mutations, which permanently inactivate followed by MET at distant sites. Recently, multiple studies in the function of E-cadherin. Reversible suppression of E-cadherin is experimental mouse models demonstrated that tumor cells need mediated by epigenetic silencing, as well as a network of to downregulate EMT inducers and regain epithelial phenotype transcriptional repressors that target the CDH1 gene promoter.38 before they can form metastatic colonies in distant organs, These EMT transcriptional repressors include Snail (Snail1),39,40 indicating that a complete EMT–MET cascade is important for 41 13 42 43,44 45 46 23,32–35 Snail2 (Slug), Twist1, Zeb1, Zeb2, Goosecoid, FOXC2, tumor metastasis. FoxQ1,47 KLF8,48 Prrx132 and many others. In this review, we will EMT and tumor dissemination have long been believed to be focus on the Snail, Twist and Zeb families of transcription factors initiated at the advanced stage of tumor progression when and provide a focused discussion of the molecular network that changes of tumor microenvironment such as hypoxia and regulate their activities in controlling EMT and cancer metastasis. inflammation induce the invasive behavior of malignant cells. However, this concept has recently been challenged by an elegant animal model in which lineage tracking was used to identify The Snail zinc finger transcription repressor family epithelial cells that have undergone EMT and disseminate to Snail family members are the most intensively studied EMT distant organs.36 In this study, EMT and cell dissemination can transcriptional repressors. A wide ranges of signaling pathways be found at pre-neoplastic stage of pancreatic tissues, and have been found to induce Snail1 and Snail2 expression including pathological conditions such as pancreatitis dramatically TGF-b,49–51 Notch52,53 and Wnt pathways,54–56
Load more

Recommended publications
  • In Vivo Studies Using the Classical Mouse Diversity Panel
    The Mouse Diversity Panel Predicts Clinical Drug Toxicity Risk Where Classical Models Fail Alison Harrill, Ph.D The Hamner-UNC Institute for Drug Safety Sciences 0 The Importance of Predicting Clinical Adverse Drug Reactions (ADR) Figure: Cath O’Driscoll Nature Publishing 2004 Risk ID PGx Testing 1 People Respond Differently to Drugs Pharmacogenetic Markers Identified by Genome-Wide Association Drug Adverse Drug Risk Allele Reaction (ADR) Abacavir Hypersensitivity HLA-B*5701 Flucloxacillin Hepatotoxicity Allopurinol Cutaneous ADR HLA-B*5801 Carbamazepine Stevens-Johnson HLA-B*1502 Syndrome Augmentin Hepatotoxicity DRB1*1501 Ximelagatran Hepatotoxicity DRB1*0701 Ticlopidine Hepatotoxicity HLA-A*3303 Average preclinical populations and human hepatocytes lack the diversity to detect incidence of adverse events that occur only in 1/10,000 people. Current Rodent Models of Risk Assessment The Challenge “At a time of extraordinary scientific progress, methods have hardly changed in several decades ([FDA] 2004)… Toxicologists face a major challenge in the twenty-first century. They need to embrace the new “omics” techniques and ensure that they are using the most appropriate animals if their discipline is to become a more effective tool in drug development.” -Dr. Michael Festing Quantitative geneticist Toxicol Pathol. 2010;38(5):681-90 Rodent Models as a Strategy for Hazard Characterization and Pharmacogenetics Genetically defined rodent models may provide ability to: 1. Improve preclinical prediction of drugs that carry a human safety risk 2.
    [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]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • MSX2 Safeguards Syncytiotrophoblast Fate of Human Trophoblast Stem Cells
    bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429538; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells Ruth Hornbachner1, Andreas Lackner1, Sandra Haider2, Martin Knöfler2, Karl Mechtler3, Paulina A. Latos1* 1Center for Anatomy and Cell Biology, Medical University of Vienna, Austria 2Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Austria 3Institute of Molecular Pathology, Vienna, Austria Short title: MSX2 in hTSCs Key words: human trophoblast stem cells, MSX2, syncytiotrophoblast, cytotrophoblast, SWI/SNF complex *correspondence: Paulina A. Latos, Center for Anatomy and Cell Biology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria; phone: 0043-1-40160-37718; e-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429538; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract The majority of placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we use human trophoblast stem cells to elucidate the function of the transcription factor MSX2 in trophoblast specification.
    [Show full text]
  • Onset of Taste Bud Cell Renewal Starts at Birth and Coincides with a Shift In
    RESEARCH ARTICLE Onset of taste bud cell renewal starts at birth and coincides with a shift in SHH function Erin J Golden1,2, Eric D Larson2,3, Lauren A Shechtman1,2, G Devon Trahan4, Dany Gaillard1,2, Timothy J Fellin1,2, Jennifer K Scott1,2, Kenneth L Jones4, Linda A Barlow1,2* 1Department of Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, United States; 2The Rocky Mountain Taste and Smell Center, University of Colorado Anschutz Medical Campus, Aurora, United States; 3Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, United States; 4Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado Anschutz Medical Campus, Aurora, United States Abstract Embryonic taste bud primordia are specified as taste placodes on the tongue surface and differentiate into the first taste receptor cells (TRCs) at birth. Throughout adult life, TRCs are continually regenerated from epithelial progenitors. Sonic hedgehog (SHH) signaling regulates TRC development and renewal, repressing taste fate embryonically, but promoting TRC differentiation in adults. Here, using mouse models, we show TRC renewal initiates at birth and coincides with onset of SHHs pro-taste function. Using transcriptional profiling to explore molecular regulators of renewal, we identified Foxa1 and Foxa2 as potential SHH target genes in lingual progenitors at birth and show that SHH overexpression in vivo alters FoxA1 and FoxA2 expression relevant to taste buds. We further bioinformatically identify genes relevant to cell adhesion and cell *For correspondence: locomotion likely regulated by FOXA1;FOXA2 and show that expression of these candidates is also LINDA.BARLOW@CUANSCHUTZ. altered by forced SHH expression.
    [Show full text]
  • Systems-Level Analysis of Cell-Specific AQP2 Gene Expression in Renal Collecting Duct
    Systems-level analysis of cell-specific AQP2 gene expression in renal collecting duct Ming-Jiun Yua, R. Lance Millerb, Panapat Uawithyaa, Markus M. Rinschena, Sookkasem Khositsetha, Drew W. W. Brauchta, Chung-Lin Choua, Trairak Pisitkuna, Raoul D. Nelsonb, and Mark A. Kneppera,1 aLaboratory of Kidney and Electrolyte Metabolism; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and bDepartment of Pediatrics, Division of Nephrology, University of Utah, Salt Lake City, UT 84132 Communicated by Peter C. Agre, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, December 22, 2008 (received for review November 9, 2008) We used a systems biology-based approach to investigate the basis for an AP2 site and Yasui et al. (12) for an AP1 site in the of cell-specific expression of the water channel aquaporin-2 (AQP2) 5Ј-flanking region of the AQP2 gene. Finally, in a mouse collecting ؅ in the renal collecting duct. Computational analysis of the 5 - duct cell line, mpkCCDc14, that expresses AQP2 mRNA and protein flanking region of the AQP2 gene (Genomatix) revealed 2 con- (14), the nuclear factor of activated T cells (NFAT) family of served clusters of putative transcriptional regulator (TR) binding transcriptional regulators (TRs) was found to be critical for tonicity- .(elements (BEs) centered at ؊513 bp (corresponding to the SF1, regulated AQP2 expression (15, 16 NFAT, and FKHD TR families) and ؊224 bp (corresponding to the Regulation of gene expression often occurs in a combinatorial AP2, SRF, CREB, GATA, and HOX TR families). Three other conserved fashion involving multiple TRs that bind to multiple closely spaced motifs corresponded to the ETS, EBOX, and RXR TR families.
    [Show full text]
  • Direct Reprogramming to Multipotent Trophoblast Stemlogo Cells, & STYLE and GUIDE Is Pluripotency Needed for Regenerative Medicine Either?31 December 2012
    Commentary Page 1 of 4 Direct reprogramming to multipotent trophoblast stemLOGO cells, & STYLE and GUIDE is pluripotency needed for regenerative medicine either?31 December 2012 Yu Yang1,2, Graham C. Parker3, Elizabeth E. Puscheck1, Daniel A. Rappolee1,2,3,4,5 1CS Mott Center for Human Growth and Development, Department of Ob/Gyn, Reproductive Endocrinology and Infertility, 2Department of Physiology, 3Department of Pediatrics and Children’s Hospital of Michigan, 4Institutes for Environmental Health Science, Wayne State University 1 School of Medicine, Detroit, MI 48201, USA; 5Department of Biology, University of Windsor, Windsor, ON N9B 3P4, Canada Correspondence to: Daniel A. Rappolee. CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 East Hancock, Detroit, MI 48201, USA. Email: [email protected]. Received: 23 April 2016; Accepted: 10 June 2016; Published: 21 June 2016. doi: 10.21037/sci.2016.06.05 View this article at: http://dx.doi.org/10.21037/sci.2016.06.05 For the clinical applications of regenerative medicine, iTSC in vitro and in vivo, as well as the transcriptome and induced pluripotent stem cells (iPSCs) (all acronyms epigenetic modification of iTSC compared with blastocyst- are defined in the Glossary at the end of the text) derived TSC (bdTSC). have advantages over embryonic stem cells (ESCs) in Of the TFs tested, three were identified in both histocompatibility and the lack of reliance on embryo reports as necessary for successful TSC induction, which derivation. Induction of pluripotency can be achieved were GATA Binding Protein 3 (Gata3), Eomesodermin by transiently expressing a minimal set of transcription (Eomes), and Transcription factor AP-2 gamma (Tfap2c).
    [Show full text]
  • Discerning the Role of Foxa1 in Mammary Gland
    DISCERNING THE ROLE OF FOXA1 IN MAMMARY GLAND DEVELOPMENT AND BREAST CANCER by GINA MARIE BERNARDO Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Adviser: Dr. Ruth A. Keri Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY January, 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Gina M. Bernardo ______________________________________________________ Ph.D. candidate for the ________________________________degree *. Monica Montano, Ph.D. (signed)_______________________________________________ (chair of the committee) Richard Hanson, Ph.D. ________________________________________________ Mark Jackson, Ph.D. ________________________________________________ Noa Noy, Ph.D. ________________________________________________ Ruth Keri, Ph.D. ________________________________________________ ________________________________________________ July 29, 2011 (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION To my parents, I will forever be indebted. iii TABLE OF CONTENTS Signature Page ii Dedication iii Table of Contents iv List of Tables vii List of Figures ix Acknowledgements xi List of Abbreviations xiii Abstract 1 Chapter 1 Introduction 3 1.1 The FOXA family of transcription factors 3 1.2 The nuclear receptor superfamily 6 1.2.1 The androgen receptor 1.2.2 The estrogen receptor 1.3 FOXA1 in development 13 1.3.1 Pancreas and Kidney
    [Show full text]
  • Predict AID Targeting in Non-Ig Genes Multiple Transcription Factor
    Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 is online at: average * The Journal of Immunology published online 20 March 2013 from submission to initial decision 4 weeks from acceptance to publication Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes Jamie L. Duke, Man Liu, Gur Yaari, Ashraf M. Khalil, Mary M. Tomayko, Mark J. Shlomchik, David G. Schatz and Steven H. Kleinstein J Immunol http://www.jimmunol.org/content/early/2013/03/20/jimmun ol.1202547 Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/suppl/2013/03/20/jimmunol.120254 7.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 26, 2021. Published March 20, 2013, doi:10.4049/jimmunol.1202547 The Journal of Immunology Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes Jamie L. Duke,* Man Liu,†,1 Gur Yaari,‡ Ashraf M. Khalil,x Mary M. Tomayko,{ Mark J. Shlomchik,†,x David G.
    [Show full text]
  • Vitamin D Signaling Pathway and Breast Cancer
    VITAMIN D SIGNALING PATHWAY AND BREAST CANCER Doctoral Thesis by Lei Sheng Vitamin D Signaling Pathway and Breast Cancer Lei Sheng M.Med., B.Med. This thesis is submitted in fulfilment of the requirements for the Doctor of Philosophy Adelaide Medical School The University of Adelaide Adelaide SA, Australia March 2017 Table of Contents Overview i Publications v Acknowledgement vii Declaration ix CHAPTER I 1 INTRODUCTION: VITAMIN D SIGNALING PATHWAY AND BREAST CANCER 1 1.1 Introduction 2 1.2 Vitamin D metabolism 2 1.2.1 The endocrine paradigm of vitamin D metabolism 2 1.2.2 The paracrine/autocrine paradigm of vitamin D metabolism 4 1.2.3 The paracrine/autocrine paradigm of vitamin D metabolism in the breast 5 1.3 Biological function of Vitamin D 6 1.3.1 The effect of vitamin D in bone 7 1.3.2 The effect of vitamin D in the murine mammary gland 8 1.3.3 The effect of vitamin D in cancer, particularly in breast cancer 10 1.4 Vitamin D and breast cancer risk 18 1.5 Vitamin D and the clinical outcome of breast cancer 20 1.6 Target genes of VDR signaling pathway 21 1.7 Conclusion 23 1.8 References 29 CHAPTER II 47 THE EFFECT OF VITAMIN D SUPPLEMENTATION ON THE RISK OF BREAST CANCER: A TRIAL SEQUENTIAL META-ANALYSIS 47 2.1 Prelude 48 2.2 Abstract 49 2.3 Introduction 51 2.4 Methods 53 2.4.1 Search strategy and eligibility criteria 53 2.4.2 Data collection 53 2.4.3 Data analysis 53 2.4.4 Trial sequential analysis 54 2.5 Results 55 2.5.1 Results of database search 55 2.5.2 Quality assessment of included trials 55 2.5.3 Effects of intervention 56
    [Show full text]
  • Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
    Downloaded from http://www.jci.org on May 2, 2017. https://doi.org/10.1172/JCI89950 The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, University of California, San Francisco, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells.
    [Show full text]
  • Supplementary Figure 1. Epigenomic Maps of Endocrine Therapy Sensitive and Resistant Cell Lines
    Supplementary Figure 1. Epigenomic maps of endocrine therapy sensitive and resistant cell lines. (A-C) ChIP-qPCR against H3K36me3 (A), H3K4me2 (B) or FAIRE-qPCR (C) was used to validate enrichment at randomly selected sites identified by ChIP-seq specific to MCF7 (left-side panel) or LTED (right-side panel) cells. Color code represents relative fold enrichment as calculated against an internal negative control. (D) Confocal analysis of immunofluorescence assay against ERα protein in MCF7-LTED HA (>12 mo) cells. Primary (prim.) and secondary (sec.) antibody controls are shown. (E) GSC analysis of the overlap between two previously published ERα cistromes and the epigenomic maps obtained in this study. Supplementary Figure 2. ERα prognostic target genes are coherently expressed in endocrine therapy resistant cell lines. (A) RT-qPCR analysis of ERα target genes across endocrine therapy-responsive or - resistant cell lines. Expression levels are normalized against MCF7 cells (dotted line). The average and SEM of replicates are shown. (B) RT-qPCR analysis of ERα expression across endocrine therapy-responsive or -resistant cell lines. Expression levels are normalized against MCF7 cells (dotted line). The average and standard error of the mean (SEM) of replicates are shown. Supplementary Figure 3. Reprogramming of the chromatin cascade increases Notch activity in endocrine therapy resistant cell lines. (A-B) RT-qPCR analysis of two γ-secretase complex subunits across endocrine therapy- responsive or -resistant cell lines. Expression levels are normalized against MCF7 cells (dotted line). The average and SEM of replicates are shown. (C-D-E) Kaplan-Meier plots of Luminal A, Luminal B or ET patients using Notch3 expression probe.
    [Show full text]