DOCSLIB.ORG

Cyp24a1 Attenuation Limits Progression of Brafv600e-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720 Minjing Zou1, Essa Y

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cyp24a1 Attenuation Limits Progression of Brafv600e-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720 Minjing Zou1, Essa Y Published OnlineFirst February 27, 2017; DOI: 10.1158/0008-5472.CAN-16-2066 Cancer Tumor and Stem Cell Biology Research Cyp24a1 Attenuation Limits Progression of BrafV600E-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720 Minjing Zou1, Essa Y. Baitei1, Huda A. BinEssa1, Futwan A. Al-Mohanna2, Ranjit S. Parhar2,ReneSt-Arnaud3, Shioko Kimura4, Catrin Pritchard5, Ali S. Alzahrani6, Abdullah M. Assiri7, Brian F. Meyer1, and Yufei Shi1 Abstract CYP24A1, the primary inactivating enzyme for vitamin D, is nocompromised nude mice. This phenotype was associated with often overexpressed in human cancers, potentially neutralizing the downregulation of the MAPK, PI3K/Akt, and TGFb signaling path- antitumor effects of calcitriol, the active form of vitamin D. How- ways and a loss of epithelial–mesenchymal transition (EMT) in ever, it is unclear whetherCYP24A1expression serves asa functional BVECyp24a1-null cells, associated with downregulation of genes contributor versus only a biomarker for tumor progression. In this involved in EMT, tumor invasion, and metastasis. While calcitriol study, we investigated the role of CYP24A1 on malignant progres- treatment did not decrease cell proliferation in BVECyp24a1-null cells, sion of a murine model of BrafV600E-induced papillary thyroid it strengthened antitumor responses to the BRAFV600E inhibitor cancer (PTC). Mice harboring wild-type Cyp24a1 (BVECyp24a1-wt) PLX4720 in both BVECyp24a1-null and BVECyp24a1-wt cells. Our find- developed PTC at 5 weeks of age. Mice harboring a homozygous ings offer direct evidence that Cyp24a1 functions as an oncogene in deletion of Cyp24a1 (BVECyp24a1-null) exhibited a 4-fold reduction PTC, where its overexpression activates multiple signaling cascades in tumor growth. Notably, we found the tumorigenic potential of to promote malignant progression and resistance to PLX4720 BVECyp24a1-null-derived tumor cells to be nearly abolished in immu- treatment. Cancer Res; 77(8); 2161–72. Ó2017 AACR. Introduction Vitamin D is mainly involved in bone and mineral metabolism. It has other important functions, such as the modulation of cell Papillary thyroid cancer (PTC) is the most common type of growth and immune function (5). Its antiproliferative effects have thyroid cancer, accounting for more than 80% of thyroid cancer attracted great enthusiasm in recent years for its potential appli- cases (1). The BRAFV600E mutation is the most frequent genetic cation as an anticancer agent. Significant antiproliferative effects alteration in PTC, occurring in 28% to 83% of cases with an have been observed in many human cancer cells, including average rate of 44% (2–4). Constitutive activation of the RAS– thyroid, prostate, breast, colorectal, and lung cancers (6–9). RAF–MEK–ERK MAP kinase signaling pathway (MAPK) promotes Vitamin D receptor (VDR) knockout mice displayed a higher the initiation and progression of PTC. incidence of carcinogen-induced breast and skin tumors (10), and vitamin D deficiency promotes human breast cancer growth (11). Although clinical trials have shown the potential therapeutic 1Department of Genetics, King Faisal Specialist Hospital and Research Centre, effects of calcitriol in prostate cancer patients (12), the success has Riyadh, Saudi Arabia. 2Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 3Department of Surgery not been convincing regarding the clinical effects of vitamin D or and Human Genetics, McGill University, Montreal, Quebec, Canada; and Research its analogues in cancer treatment (13, 14). This may be due to the Centre, Shriners Hospitals for Children, Montreal, Quebec, Canada. 4Laboratory overexpression of CYP24A1 in many cancer patients. of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Vitamin D 24-hydroxylase (CYP24A1) is the primary vitamin Maryland. 5Department of Biochemistry, University of Leicester, Lancaster Road, D-inactivating enzyme, which catabolizes 1a, 25(OH)2D3 (calci- Leicester, UK. 6Department of Medicine, King Faisal Specialist Hospital and 7 triol) and, to a lesser extent, 25(OH)2D3 by 24 hydroxylation into Research Centre, Riyadh, Saudi Arabia. Department of Comparative Medicine, a King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. inactive 1 , 24,25(OH)3D3 and 24,25(OH)2D3 (6). The calci- triol-mediated antiproliferative effects could be disrupted by Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). CYP24A1 overexpression during tumor development (7). Indeed, CYP24A1 overexpression has been observed in many cancers, M. Zou and E.Y. Baitei contributed equally to this article. including thyroid (15, 16), lung (17), colon (18), esophageal Corresponding Author: Yufei Shi, King Faisal Specialist Hospital and Research (19), and breast (20), and has been linked to poor prognosis in Centre, MBC#3, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Phone: 966-1-442- patients with lung (21), esophageal (19), colon (22), and thyroid 4768; Fax: 966-1-442-4585; E-mail: [email protected] (16, 23) cancers. It has been proposed as a candidate oncogene doi: 10.1158/0008-5472.CAN-16-2066 due to its gene amplification in breast cancer (24). In patients Ó2017 American Association for Cancer Research. with thyroid cancer, the serum calcitriol level was found to be www.aacrjournals.org 2161 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 27, 2017; DOI: 10.1158/0008-5472.CAN-16-2066 Zou et al. significantly lower (25), although there was no significant differ- allele of 250 bp, and primers 1 þ 3 detected the mutant allele ence in the serum 25(OH) D3 level between thyroid nodule and of 600 bp. The PCR conditions were as follows: 94 C for 5 minutes thyroid cancer patients (25, 26), indicating that calcitriol might be followed by 35 cycles of amplification (94C for 30 seconds, 58C converted to inactive 1a, 24,25(OH)3D3 by increased CYP24A1 for 30 seconds, 72 C for 1 minutes) with a final extension at 72 C expression. Although these data suggest that CYP24A1 overexpres- for 10 minutes. sion could result in the abrogation of calcitriol-mediated growth arrest leading to tumor development and/or progression, there are Establishment of thyroid tumor cell lines no in vivo functional studies to support this hypothesis. Thyroid tumors were collected aseptically from donor mice In our previous study, we demonstrated that CYP24A1 over- (BVECyp24a1-wt and BVECyp24a1-null) using blunt dissection, then V600E expression was associated with BRAF mutation and advanced mechanically dissociated by mincing and passing through a 40- V600E stages of PTC (23). We also showed that BRAF induced mm/mesh sterile screen, and suspended in DMEM/F12 growth V600E CYP24A1 overexpression and the BRAF inhibitor PLX4720 medium (10% fetal bovine serum, 100 units/mL penicillin, 100 fi signi cantly enhanced the antiproliferative effects of calcitriol in mg/mL streptomycin). The cells were further dissociated by incu- thyroid cancer cell lines (23). However, it is not clear to what extent bation in growth medium containing 100 U/mL type I collage- CYP24A1 overexpression contributes to thyroid cancer develop- nase (Sigma-Aldrich) and 1.0 U/mL dispase I (Roche Diagnostics) ment and progression in vivo, especially in the presence of at 37C in a rocking water bath for 60 minutes. The cell suspension V600E BRAF . In the present study, we used a mouse model of was washed twice with growth media and resuspended in a 10- V600E Braf -induced PTC to investigate the role of Cyp24a1 in thyroid mm culture dish with DMEM/F12 growth medium containing 4 cancer progression. We observed that thyroid cancer growth was mU/mL bovine TSH (Sigma-Aldrich) to establish BVECyp24a1-wt fi signi cantly reduced in the absence of Cyp24a1 expression. and BVECyp24a1-null cell lines. The established cell lines were propagated in DMEM/Ham's F12 growth medium. Two cell Materials and Methods lines were established each from two separate BVECyp24a1-wt or BVECyp24a1-null primary thyroid tumors in 2015: BVECyp24a1-wt-1, Animals BVECyp24a1-wt-2, BVECyp24a1-null-1, and BVECyp24a1-null-2. The thy- – V600E The generation of TPO Braf and Cyp24a1 knockout mice roid origin of these cell lines was confirmed by genotyping in the (Cyp24a1null) have been described previously (27–29). TPO- V600E Cyp24a1-wt lab as described above, which was performed 1 month before Braf mice with wild-type Cyp24a1 (BVE ) developed using the cell lines. PTC at approximately 5 weeks of age and were used as PTC tumor controls. TPO-BrafWT mice with wild-type Cyp24a1 were used as Cyp24a1 normal controls. TPO-BrafV600E mice with Cyp24a1 knockout Quantitative real-time RT-PCR analysis for expression (BVECyp24a1-null) were obtained by several rounds of breeding Total RNA was isolated from the thyroid tumor tissues of þ À Cyp24a1-wt Cyp24a1-null among LSL-BrafV600E(30) TPO-Cre (31), and Cyp24a1 / mice. BVE mice and BVE mice by the quanidinium – – Because 50% of the homozygous mutant Cyp24a1null mice died thiocyanate phenol chloroform method (32). The integrity of fi before 3 weeks of age (29), the mice were kept in a heterozygous the RNA was veri ed by denaturing gel electrophoresis. Two þ À m state (Cyp24a1 / ). To knockout Cyp24a1 in TPO–BrafV600E mice, micrograms ( g) of each total RNA was reverse-transcribed to þ À Cyp24a1 / mice were first crossed with LSL–BrafV600E or TPO– cDNA using the Promega RT system (Promega). The LightCycler þ À Cre mice to generate a Cyp24a1 / ; BrafV600E strain or TPO–Cre; DNA Master SYBR Green 1 Kit was used for quantitative real-time þ À þ À m Cyp24a1 / strain. Cyp24a1 / ; BrafV600E mice and TPO–Cre; PCR analysis (33). The cDNA mix was diluted 10-fold, and 2 Lof þ/À – the dilution was used for real-time PCR analysis. The PCR primers Cyp24a1 mice were then bred together to create TPO 0 V600E– À/À or null for the 126-bp Cyp24a1 cDNA fragment were: 5 -CATCGCAAC- Braf Cyp24a1 mice.
Load more

Recommended publications
  • Homeobox Gene Expression Profile in Human Hematopoietic Multipotent
    Leukemia (2003) 17, 1157–1163 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development T Taghon1, K Thys1, M De Smedt1, F Weerkamp2, FJT Staal2, J Plum1 and G Leclercq1 1Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium; and 2Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands Class I homeobox (HOX) genes comprise a large family of implicated in this transformation proces.14 The HOX-C locus transcription factors that have been implicated in normal and has been primarily implicated in lymphomas.15 malignant hematopoiesis. However, data on their expression or function during T-cell development is limited. Using degener- Hematopoietic cells are derived from stem cells that reside in ated RT-PCR and Affymetrix microarray analysis, we analyzed fetal liver (FL) in the embryo and in the adult bone marrow the expression pattern of this gene family in human multipotent (ABM), which have the unique ability to self-renew and thereby stem cells from fetal liver (FL) and adult bone marrow (ABM), provide a life-long supply of blood cells. T lymphocytes are a and in T-cell progenitors from child thymus. We show that FL specific type of hematopoietic cells that play a major role in the and ABM stem cells are similar in terms of HOX gene immune system. They develop through a well-defined order of expression, but significant differences were observed between differentiation steps in the thymus.16 Several transcription these two cell types and child thymocytes.
    [Show full text]
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
    [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]
  • Expression Pattern of the Class I Homeobox Genes in Ovarian Carcinoma
    J Gynecol Oncol Vol. 21, No. 1:29-37, March 2010 DOI:10.3802/jgo.2010.21.1.29 Original Article Expression pattern of the class I homeobox genes in ovarian carcinoma Jin Hwa Hong1, Jae Kwan Lee1, Joong Jean Park2, Nak Woo Lee1, Kyu Wan Lee1, Jung Yeol Na1 Departments of 1Obstetrics and Gynecology, 2Physiology, Korea University College of Medicine, Seoul, Korea Objective: Although some sporadic reports reveal the link between the homeobox (HOX) genes and ovarian carcinoma, there is no comprehensive analysis of the expression pattern of the class I homeobox genes in ovarian carcinoma that determines the candidate genes involved in ovarian carcinogenesis. Methods: The different patterns of expression of 36 HOX genes were analyzed, including 4 ovarian cancer cell lines and 4 normal ovarian tissues. Using a reverse transcription-polymerase chain reaction (RT-PCR) and quantification analysis, the specific gene that showed a significantly higher expression in ovarian cancer cell lines than in normal ovaries was selected, and western blot analysis was performed adding 7 ovarian cancer tissue specimens. Finally, immunohistochemical and immunocytochemical analyses were performed to compare the pattern of expression of the specific HOX gene between ovarian cancer tissue and normal ovaries. Results: Among 36 genes, 11 genes had a different level of mRNA expression between the cancer cell lines and the normal ovarian tissues. Of the 11 genes, only HOXB4 had a significantly higher level of expression in ovarian cancer cell lines than in normal ovaries (p=0.029). Based on western blot, immunohistochemical, and immunocytochemical analyses, HOXB4 was expressed exclusively in the ovarian cancer cell lines or cancer tissue specimens, but not in the normal ovaries.
    [Show full text]
  • Motor Neuron Columnar Fate Imposed by Sequential Phases of Hox-C Activity
    articles Motor neuron columnar fate imposed by sequential phases of Hox-c activity Jeremy S. Dasen1, Jeh-Ping Liu2 & Thomas M. Jessell1 1Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, 701 West 168th Street, New York, New York 10032, USA 2University of Virginia School of Medicine, Department of Neuroscience, Lane Road extended, MR4, Room 5032, Charlottesville, Virginia 22908, USA ........................................................................................................................................................................................................................... The organization of neurons into columns is a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded fibroblast growth factor signalling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization. Columns are basic units of neuronal organization in the vertebrate neural Hox protein expression, and the establishment of spinal MN central nervous system (CNS)1,2, but the mechanisms that control columnar identity, if any, remains obscure. their assembly remain unclear.
    [Show full text]
  • Supplementary Material Computational Prediction of SARS
    Supplementary_Material Computational prediction of SARS-CoV-2 encoded miRNAs and their putative host targets Sheet_1 List of potential stem-loop structures in SARS-CoV-2 genome as predicted by VMir. Rank Name Start Apex Size Score Window Count (Absolute) Direct Orientation 1 MD13 2801 2864 125 243.8 61 2 MD62 11234 11286 101 211.4 49 4 MD136 27666 27721 104 205.6 119 5 MD108 21131 21184 110 204.7 210 9 MD132 26743 26801 119 188.9 252 19 MD56 9797 9858 128 179.1 59 26 MD139 28196 28233 72 170.4 133 28 MD16 2934 2974 76 169.9 71 43 MD103 20002 20042 80 159.3 403 46 MD6 1489 1531 86 156.7 171 51 MD17 2981 3047 131 152.8 38 87 MD4 651 692 75 140.3 46 95 MD7 1810 1872 121 137.4 58 116 MD140 28217 28252 72 133.8 62 122 MD55 9712 9758 96 132.5 49 135 MD70 13171 13219 93 130.2 131 164 MD95 18782 18820 79 124.7 184 173 MD121 24086 24135 99 123.1 45 176 MD96 19046 19086 75 123.1 179 196 MD19 3197 3236 76 120.4 49 200 MD86 17048 17083 73 119.8 428 223 MD75 14534 14600 137 117 51 228 MD50 8824 8870 94 115.8 79 234 MD129 25598 25642 89 115.6 354 Reverse Orientation 6 MR61 19088 19132 88 197.8 271 10 MR72 23563 23636 148 188.8 286 11 MR11 3775 3844 136 185.1 116 12 MR94 29532 29582 94 184.6 271 15 MR43 14973 15028 109 183.9 226 27 MR14 4160 4206 89 170 241 34 MR35 11734 11792 111 164.2 37 52 MR5 1603 1652 89 152.7 118 53 MR57 18089 18132 101 152.7 139 94 MR8 2804 2864 122 137.4 38 107 MR58 18474 18508 72 134.9 237 117 MR16 4506 4540 72 133.8 311 120 MR34 10010 10048 82 132.7 245 133 MR7 2534 2578 90 130.4 75 146 MR79 24766 24808 75 127.9 59 150 MR65 21528 21576 99 127.4 83 180 MR60 19016 19049 70 122.5 72 187 MR51 16450 16482 75 121 363 190 MR80 25687 25734 96 120.6 75 198 MR64 21507 21544 70 120.3 35 206 MR41 14500 14542 84 119.2 94 218 MR84 26840 26894 108 117.6 94 Sheet_2 List of stable stem-loop structures based on MFE.
    [Show full text]
  • Mammalian-Specific Ectodermal Enhancers Control the Expression of Hoxc Genes in Developing Nails and Hair Follicles
    Mammalian-specific ectodermal enhancers control the expression of Hoxc genes in developing nails and hair follicles Marc Fernandez-Guerreroa, Nayuta Yakushiji-Kaminatsuib,1, Lucille Lopez-Delisleb, Sofía Zdrala, Fabrice Darbellayb,2, Rocío Perez-Gomeza, Christopher Chase Boltb, Manuel A. Sanchez-Martinc, Denis Dubouleb,d,e,3, and Marian A. Rosa,f,3 aInstituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas–Universidad de Cantabria–Sociedad para el Desarrollo de Cantabria, 39011 Santander, Spain; bSchool of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland; cDepartment of Medicine, University of Salamanca, 37007 Salamanca, Spain; dDepartment of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland; eCollège de France, Paris, France; and fDepartamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain Contributed by Denis Duboule, October 6, 2020 (sent for review June 1, 2020; reviewed by Nadav Ahituv and Robert Hill) Vertebrate Hox genes are critical for the establishment of structures and thus to show less functional redundancy. Examples of this during the development of the main body axis. Subsequently, they situation may be found either in the function of some Hoxa genes play important roles either in organizing secondary axial structures in uterine physiology (9–11) or in the apparent specialization of such as the appendages, or during homeostasis in postnatal stages some Hoxc genes for epidermal derivatives (12, 13), while other and adulthood. Here, we set up to analyze their elusive function in clusters apparently do not play any detectable function there. the ectodermal compartment, using the mouse limb bud as a model.
    [Show full text]
  • Differentiation and Cell-Type-Restricted Expression of HOXC4, HOXCS and HOXC6 M Myeloid Leukemias and Normal Myeloid Cells
    Leukemia 11998) 12, 1724-1 732 © 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 1724 http://www.stockton-press.eo.uk/leu Differentiation and cell-type-restricted expression of HOXC4, HOXCS and HOXC6 m myeloid leukemias and normal myeloid cells 1 2 1 2 1 JJ Bijl , JW van Oostveen , JMM Walboomers', ATP Brink', W Vos , GJ Ossenkoppele and C)LM Meijer ' Department of Pathology and 'Department of Hematology, Academic Hospital of the Vrije Universiteit, Amsterdam, The Netherlands HOX genes have shown a lineage-specific expression in hema­ eage-restricted expression pattern s of HOX genes were found topoiesis and are suggested as being involved in the 5 6 in hematopoietic cells. · HOXC genes are found to be expression of certain adhesion molecules. Recently, we have expressed in human and mouse lymphocytic and myeloid cell demonstrated that HOXC4 and HOXC6, but not HOXC5, are 5 7 9 expressed during lymphoid differentiation. Reports on the lines. • - It appeared that from these genes HOXC8 was expression of these genes in myeloid leukemias and normal ubiquitously expressed in lymphoid, myeloid, erythroid and myeloid cells are still scarce. Therefore, we have investigated megakaryocytic cell lines. Expression of HO XC4 was found the expression of HOXC4, HOXC5 and HOXC6 in purified sub­ to be restricted to lymphoid cells.7 However, the reported data populations of bone marrow in addition to 36 specimens of are obtained by techniques with different sensitivity levels, acute myeloid leukemias (AMLs), eight chronic myeloid leuke­ hindering a reliable comparison. Therefore, we applied a mias (CMLs), several myeloid cell lines and cutaneous localiza­ 10 tions of three myelomonocytic leukemias and one granulocytic sensitive RT-PCR specific for HOXC4, HOXCS and HOXC6.
    [Show full text]
  • Epigenetic Biomarkers in Obesity, Weight Loss and Inflammation: a Role for Circadian Rhythm and Methyl Donors
    Facultad de Farmacia y Nutrición Epigenetic biomarkers in obesity, weight loss and inflammation: a role for circadian rhythm and methyl donors Mirian Samblas García Pamplona, 2018 Facultad de Farmacia y Nutrición Memoria presentada por Dña. Mirian Samblas García para aspirar al grado de Doctor por la Universidad de Navarra. Mirian Samblas García El presente trabajo ha sido realizado bajo nuestra dirección en el Departamento de Ciencias de la Alimentación y Fisiología de la Facultad de Farmacia y Nutrición de la Universidad de Navarra y autorizamos su presentación ante el Tribunal que lo ha de juzgar. Pamplona, 26 de Febrero de 2018 VºBº Director VºBº Co-Director Dr. Fermín I. Milagro Yoldi Prof. J. Alfredo Martínez Hernández Este trabajo ha sido posible gracias a la financiación de diversas entidades: Ministerio de Economía y Competitividad (AGL2013-45554-R), Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituo de Salud Carlos III (ISCIII), Centro de Investigación en Nutrición (Universidad de Navarra). La investigación que ha dado lugar a estos resultados ha sido impulsada por la beca predoctoral 2014-2015 del Centro de Investigación en Nutrición y las becas predoctoral 2015-2018 y de movilidad del Ministerio de Educación, Cultura y Deporte. “Necesitamos especialmente de la imaginación en las ciencias. No todo es matemáticas y no todo es simple lógica, también se trata de un poco de belleza y poesía” Maria Montessori Dedicado a las dos personas que me lo han dado todo, Mi aita Ray, Mi ama Ana Con especial cariño a, Mi hermana, Bea Mi sobrina, Aroa Mi abu, Esther Agradecimientos/Acknowledgements En estas líneas quisiera mostrar mi más sincero agradecimiento a todas aquellas personas e instituciones que han hecho posible la actual tesis.
    [Show full text]
  • BMC Biology Biomed Central
    BMC Biology BioMed Central Research article Open Access Classification and nomenclature of all human homeobox genes PeterWHHolland*†1, H Anne F Booth†1 and Elspeth A Bruford2 Address: 1Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK and 2HUGO Gene Nomenclature Committee, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK Email: Peter WH Holland* - [email protected]; H Anne F Booth - [email protected]; Elspeth A Bruford - [email protected] * Corresponding author †Equal contributors Published: 26 October 2007 Received: 30 March 2007 Accepted: 26 October 2007 BMC Biology 2007, 5:47 doi:10.1186/1741-7007-5-47 This article is available from: http://www.biomedcentral.com/1741-7007/5/47 © 2007 Holland et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The homeobox genes are a large and diverse group of genes, many of which play important roles in the embryonic development of animals. Increasingly, homeobox genes are being compared between genomes in an attempt to understand the evolution of animal development. Despite their importance, the full diversity of human homeobox genes has not previously been described. Results: We have identified all homeobox genes and pseudogenes in the euchromatic regions of the human genome, finding many unannotated, incorrectly annotated, unnamed, misnamed or misclassified genes and pseudogenes.
    [Show full text]
  • Transforming Growth Factor ß1-Mediated Functional Inhibition Of
    Myelodysplastic Syndromes SUPPLEMENTARY APPENDIX Transforming growth factor 1- mediated functional inhibition of mesenchymal stromal celβls in myelodysplastic syndromes and acute myeloid leukemia Stefanie Geyh, 1* Manuel Rodríguez-Paredes, 1,2 * Paul Jäger, 1 Annemarie Koch, 1 Felix Bormann, 2 Julian Gutekunst, 2 Christoph Zilkens, 3 Ulrich Germing, 1 Guido Kobbe, 1 Frank Lyko, 2 Rainer Haas 1 and Thomas Schroeder 1 1Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty; 2Division of Epigenetics, DKFZ- ZMBH Alliance, German Cancer Research Center, Heidelberg and 3Department of Orthopedic Surgery, University of Duesseldorf, Medical Faculty, Germany *SG and MR-P contributed equally to this work. ©2018 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2017.186734 Received: December 19, 2017. Accepted: May 14, 2018. Pre-published: May 17, 2018. Correspondence: [email protected] Figure S1 Downregulated genes Downregulated genes Upregulated Figure S1. Heatmaps showing the 50 most upregulated and downregulated genes between the 3 healthy MSC controls and the 9 RCMD-, RAEB- and AML-derived MSC samples. Color scale depicts the rlog-transformed FPKM values for each gene and every sample. Figure S2 Downregulated genes Downregulated genes Upregulated Figure S2. Heatmaps showing the 50 most upregulated and downregulated genes between the 3 healthy MSC controls and the 3 RCMD, RAEB and AML MSC samples, respectively. Color scales depict the rlog-transformed FPKM values for each gene and every sample. Figure S3 A. B. 0.0015 *** ** <-3 -2 0.0010 RCMD RAEB AML -1 0 1 0.0005 Log2FC LTF 2 CCL26/GAPDH INHBB >3 0.0000 TGFB2 y S h D ML M A ealt ll LTF H a EGF 0.003 *** ** INHBB TGFB2 0.002 INHBB IGFBP7 0.001 GDF11 LIF/GAPDH BMP1 0.000 y L th M TNFSF12 l A FGF13 ea ll MDS H a FGF13 0.0015 * TNFSF10 TNFSF10 0.0010 0.0005 SPP1/GAPDH 0.0000 y th l AML ea H all MDS Figure S3.
    [Show full text]
  • 1 Specific Ectodermal Enhancers Control The
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.10.143677; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SPECIFIC ECTODERMAL ENHANCERS CONTROL THE EXPRESSION OF Hoxc GENES IN DEVELOPING MAMMALIAN INTEGUMENTS. Marc Fernandez-Guerrero1, Nayuta Yakushiji-Kaminatsui2,‡, Lucille Lopez-Delisle2, Sofía Zdral1, Fabrice Darbellay2,+, Rocío Perez-Gomez1, Christopher Chase Bolt2, Manuel A. Sanchez-Martin3, Denis Duboule2,4,5,* and Maria A. Ros1,6,*. 1Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC-U SODERCAN). Albert Einstein 22. 39011, Santander, Spain. 2School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland. 3Department of Medicine. University of Salamanca. Campus Miguel de Unamuno s/n. 37007 Salamanca, Spain. 4Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland. 5Collège de France, Paris, France. 6Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain Present addresses: ‡ Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. +Environmental Genomics and Systems Biology Division, Lawrence Berkeley Laboratories, Berkeley, United States * Marian Ros ([email protected]), * Denis Duboule ([email protected]) Keywords Hox genes, colinearity, nails, hairs, enhancers, ECTD syndromes. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.10.143677; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
    [Show full text]