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Ichiro Kaneko Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA
Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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Rimpi K Saini Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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Kristin P Griffin Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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G Kerr Whitfield Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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Mark R Haussler Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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Peter W Jurutka Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA
Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USA

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In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor 23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression and induces C/EBPβ, but does not affect leptin receptor transcription. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a fourfold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate vitamin D receptor (VDR)/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1–VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1 kb mouse FGF23 promoter–reporter construct, transfected into MC3T3-E1 osteoblast-like cells, responds to a high calcium challenge with a statistically significant 1.7- to 2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

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J. A. Franklyn
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M. C. Sheppard
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Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham b15 2th

received 1 November 1987

Introduction

Thyrotrophin (TSH) is one of a family of glycoprotein hormones which includes the pituitary hormones follicle-stimulating hormone and luteinizing hormone, and placental chorionic gonadotrophin. Each hormone is composed of two dissimilar, non-covalently linked glycosylated subunits, α and β. The mammalian genome contains a single gene encoding the α-subunit which is common to each of the glycoprotein hormones (Fiddes & Goodman, 1981). In contrast, the β-subunits of each hormone are encoded by different genes and confer biological and immunological specificity upon the intact dimer.

The gene encoding the β-subunit of TSH has been assigned to chromosome 1 in man (Fukushige, Murotsu & Matsubara, 1986) and chromosome 3 in the mouse (Kourides, Barker, Gurr et al. 1984). The α-gene, unlike the β-gene, has been assigned in the mouse to chromosome 4 (Kourides et al.

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Celia Siu Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada
Department of Sciences, University of British Columbia, Vancouver, Canada

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Sam Wiseman Department of Surgery, St. Paul’s Hospital & University of British Columbia, Vancouver, Canada

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Sitanshu Gakkhar Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Alireza Heravi-Moussavi Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Misha Bilenky Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Annaick Carles Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, Canada

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Thomas Sierocinski Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, Canada

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Angela Tam Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Eric Zhao Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Katayoon Kasaian Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Richard A Moore Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Andrew J Mungall Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada

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Blair Walker Department of Pathology and Laboratory Medicine, St. Paul’s Hospital & University of British Columbia, Vancouver, Canada

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Thomas Thomson Department of Pathology and Laboratory Medicine, BC Cancer Agency & University of British Columbia, Vancouver, Canada

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Marco A Marra Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada
Department of Medical Genetics, University of British Columbia, Vancouver, Canada

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Martin Hirst Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada
Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, Canada

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Steven J M Jones Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada
Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, Canada

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unique feature of the thyroid or terminally differentiated tissues. It is possible that the states are much more consistent in developing and pluripotent cells where gene regulation may need to be under more stringent control. Using HMMs to partition

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David W Scoville Cell Biology Group, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

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Kristin Lichti-Kaiser Cell Biology Group, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

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Sara A Grimm Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

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Anton M Jetten Cell Biology Group, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

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-specific transcription factors may then coordinate their transcriptional regulation through coactivator protein complexes recruited to these regulatory hubs. In summary, our study provides the first in-depth characterization of the role of GLIS3 in gene regulation

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Gabriela Hernández-Puga Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico

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Arturo Mendoza Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico

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Alfonso León-del-Río Programa de Investigación de Cáncer de Mama y Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, UNAM, México, Mexico

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Aurea Orozco Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico

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previously identified as a coactivator of several liganded NRs, including TRa1 ( Chauchereau et al . 2000 ). Our study shows that Jab1 exhibits opposite roles upon gene regulation. As we found Jab1 to be bound to L-Trb1 in the presence of T 2

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Xiao-Bing Cui Department of Physiology and Pharmacology, Renmin Hospital, Antioxidant and Gene Regulation Laboratory, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USA

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Jun-Na Luan Department of Physiology and Pharmacology, Renmin Hospital, Antioxidant and Gene Regulation Laboratory, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USA

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Jianping Ye Department of Physiology and Pharmacology, Renmin Hospital, Antioxidant and Gene Regulation Laboratory, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USA

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Shi-You Chen Department of Physiology and Pharmacology, Renmin Hospital, Antioxidant and Gene Regulation Laboratory, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USA
Department of Physiology and Pharmacology, Renmin Hospital, Antioxidant and Gene Regulation Laboratory, University of Georgia, 501 D.W. Brooks Drive, Athens, Georgia 30602, USA

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Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32 −/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32 −/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32 −/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

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Denis Stygar Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Q2:08, S-171 76 Stockholm, Sweden

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Britt Masironi Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Q2:08, S-171 76 Stockholm, Sweden

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Håkan Eriksson Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Q2:08, S-171 76 Stockholm, Sweden

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Lena Sahlin Division for Reproductive Endocrinology, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Q2:08, S-171 76 Stockholm, Sweden

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E 2 (as shown in Fig. 2 ), which could indicate that mechanisms of gene regulation by PPTand DPN may be substantially different from the mechanism of E 2 action. There is a possibility that the treatments themselves may have had an effect on the

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Kotaro Azuma Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Stephanie C Casey Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Masako Ito Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Tomohiko Urano Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Kuniko Horie Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Yasuyoshi Ouchi Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Séverine Kirchner Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Bruce Blumberg Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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Satoshi Inoue Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Department of Geriatric Medicine, Department of Developmental and Cell Biology, Division of Radiology, Department of Anti-Aging Medicine, Division of Gene Regulation and Signal Transduction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

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The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.

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Chun Zeng Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Xin Yi Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Danny Zipris Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Hongli Liu Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Lin Zhang Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Qiaoyun Zheng Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Krishnamurthy Malathi Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Ge Jin Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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Aimin Zhou Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA
Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA
Clinical Chemistry Program, Center for Gene Regulation in Health and Diseases, Department of Cancer Biology, Barbara Davis Center of Childhood Diabetes, Central Laboratory, Department of Biological Sciences, Department of Biological Sciences, Department of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USA

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The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.

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A McMaster Medicine, Faculty of Life Sciences, Centre for Molecular
Medicine, Faculty of Life Sciences, Centre for Molecular

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T Chambers Medicine, Faculty of Life Sciences, Centre for Molecular

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Q-J Meng Medicine, Faculty of Life Sciences, Centre for Molecular

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S Grundy Medicine, Faculty of Life Sciences, Centre for Molecular

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A S I Loudon Medicine, Faculty of Life Sciences, Centre for Molecular

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R Donn Medicine, Faculty of Life Sciences, Centre for Molecular
Medicine, Faculty of Life Sciences, Centre for Molecular

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D W Ray Medicine, Faculty of Life Sciences, Centre for Molecular

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There is increasing evidence that temporal factors are important in allowing cells to gain additional information from external factors, such as hormones and cytokines. We sought to discover how cell responses to glucocorticoids develop over time, and how the response kinetics vary according to ligand structure and concentration, and hence have developed a continuous gene transcription measurement system, based on an interleukin-6 (IL-6) luciferase reporter gene. We measured the time to maximal response, maximal response and integrated response, and have compared these results with a conventional, end point glucocorticoid bioassay. We studied natural glucocorticoids (corticosterone and cortisol), synthetic glucocorticoids (dexamethasone) and glucocorticoid precursors with weak, or absent bioactivity. We found a close correlation between half maximal effective concentration (EC50) for maximal response, and for integrated response, but with consistently higher EC50 for the latter. There was no relation between the concentration of ligand and the time to maximal response. A comparison between conventional end point assays and real-time measurement showed similar effects for dexamethasone and hydrocortisone, with a less effective inhibition of IL-6 seen with corticosterone. We profiled the activity of precursor steroids, and found pregnenolone, progesterone, 21-hydroxyprogesterone and 17-hydroxyprogesterone all to be ineffective in the real-time assay, but in contrast, progesterone and 21-hydroxyprogesterone showed an IL-6 inhibitory activity in the end point assay. Taken together, our data show how ligand concentration can alter the amplitude of glucocorticoid response, and also that a comparison between real-time and end point assays reveals an unexpected diversity of the function of glucocorticoid precursor steroids, with implications for human disorders associated with their overproduction.

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