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      Functional Evidence for the Presence of Type II 5’-Deiodinase in Somatotropes and Its Adaptive Role in Hypothyroidism

      ,

      Neuroendocrinology

      S. Karger AG

      5′-Deiodinase, Thyroid hormones, Growth hormone, Somatotropes

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          Abstract

          The anterior pituitary contains abundant type II iodothyronine 5′-deiodinase (D2). The role of this enzyme in mediating thyroid hormone action in the pituitary has been proven only for thyrotropes, although there is evidence that it exists in other cell types, including somatotropes and lactotropes. Here we investigated the potential of D2 to mediate thyroid hormone regulation of growth hormone (GH). Using GH mRNA as an end point, we demonstrate that in hyperthyroid states GH mRNA levels are stimulated by triiodothyronine (T<sub>3</sub>) generated via D1, whereas in hypothyroidism, when D2 activity is markedly increased, GH mRNA is more responsive to tetraiodothyronine (T<sub>4</sub>) in a propylthiouracil-insensitive, reverse T<sub>3</sub>-suppressible manner. Under short-term hyperthyroid conditions, GH levels correlate with plasma T<sub>3</sub>; in contrast, the correlation is not observed in hypothyroidism, a condition in which plasma T<sub>3</sub> levels are too low to account for the response. These results add support to the concept that D2 is present in the pituitary and that the enzyme plays an important role in mediating stimulation of GH by thyroid hormones, particularly in hypothyroid states in which they could alleviate the impact of hypothyroxinemia on GH secretion.

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          Most cited references 3

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Type I iodothyronine deiodinase is a selenocysteine-containing enzyme.

            Although thyroxine (3,5,3',5'-tetraiodothyronine, T4) is the principal secretory product of the vertebrate thyroid, its essential metabolic and developmental effects are all mediated by 3,5,3'-triiodothyronine (T3), which is produced from the prohormone by 5'-deiodination. The type-I iodothyronine deiodinase, a thiol-requiring propylthiouracil-sensitive oxidoreductase, is found mainly in liver and kidney and provides most of the circulating T3(1) but so far this enzyme has not been purified. Using expression cloning in the Xenopus oocyte, we have isolated a 2.1-kilobase complementary DNA for this deiodinase from a rat liver cDNA library. The kinetic properties of the protein expressed in transient assay systems, the tissue distribution of the messenger RNA, and its changes with thyroid status, all confirm its identity. We find that the mRNA for this enzyme contains a UGA codon for selenocysteine which is necessary for maximal enzyme activity. This explains why conversion of T4 to T3 is impaired in experimental selenium deficiency and identifies an essential role for this trace element in thyroid hormone action.
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              Cloning and expression of a cDNA for a mammalian type III iodothyronine deiodinase.

              The type III iodothyronine deiodinase metabolizes the active thyroid hormones thyroxine and 3,5,3'-triiodothyronine to inactive compounds. Recently, we have characterized a Xenopus laevis cDNA (XL-15) that encodes a selenoprotein with type III deiodinase activity (St. Germain, D.L., Schwartzman, R., Croteau, W., Kanamori, A., Wang, Z., Brown, D.D., and Galton, V.A. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 7767-7771). Using the XL-15 as a probe, we screened a rat neonatal skin cDNA library. Among the clones isolated was one (rNS43-1) which contained a 2.1-kilobase pair cDNA insert that manifested significant homology to both the XL-15 and the G21 rat type I deiodinase cDNAs, including the presence of an in-frame TGA codon. Expression studies demonstrated that the rNS43-1 cDNA encodes a protein with 5-, but not 5'-, deiodinase activity that is resistant to inhibition by propylthiouracil and aurothioglucose. Northern analysis demonstrated a pattern of tissue expression in the rat consistent with that of the type III deiodinase and site directed mutagenesis confirmed that the TGA triplet codes for selenocysteine. We conclude that the rNS43-1 cDNA encodes the rat type III deiodinase and that the types I and III deiodinases present in amphibians and mammals constitute a family of conserved selenoproteins important in the metabolism of thyroid hormones.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2001
                October 2001
                05 October 2001
                : 74
                : 4
                : 220-226
                Affiliations
                Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil
                Article
                54689 Neuroendocrinology 2001;74:220–226
                10.1159/000054689
                11598378
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 1, References: 40, Pages: 7
                Categories
                Regulation of Growth Hormone

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