scholarly journals Impact of Gene Cloning, Disruption and Over-Expression of Iodothyronine Deiodinases on Thyroid Hormone Homeostasis

2002 ◽  
Vol 46 (4) ◽  
pp. 402-411
Author(s):  
Antonio C. Bianco
Keyword(s):  
Thyroid Hormone ◽  
Physiological Plasticity ◽  
Targeted Disruption ◽  
Over Expression ◽  
Phenolic Ring ◽  
Iodothyronine Deiodinases ◽  
Thyroid Hormone Action ◽  
Hormone Homeostasis ◽  
Thyroid Secretion ◽  
Made In

Thyroxine (T4) is the main product of thyroid secretion, a pro-hormone that must be activated by deiodination to T3 in order to initiate thyroid hormone action. This deiodination reaction occurs in the phenolic-ring (outer-ring deiodination, ORD) of the T4 molecule and is catalyzed by two selenocysteine-containing deiodinases, i.e. D1 and D2. As a counter point to the activation pathway, both T4 and T3 can be irreversibly inactivated by deiodination of the thyrosyl-ring (inner-ring deiodination, IRD), a reaction catalyzed by D3, the third member of the selenodeiodinase group. Due to its substantial physiological plasticity, D2 is considered the critical T3-producing deiodinase in humans. Recently, the observations made in the D1-deficient C3H mouse mice were expanded by the development of mice with generalized targeted disruption or cardiac-specific over-expression of the D2 gene. The results obtained indicate that the selenodeiodinases constitute a physiological system contributing with the thyroid hormone homeostasis during adaptation to changes in iodine supply, cold exposure, in patients with thyroid dysfunction and perhaps during starvation and illness.

scholarly journals The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis

2002 ◽  
Vol 175 (1) ◽  
pp. 61-73 ◽  
Author(s):  
G Schreiber
Keyword(s):  
Thyroid Hormone ◽  
Choroid Plexus ◽  
Molecular Mechanism ◽  
Amino Acid Sequences ◽  
Open Reading Frames ◽  
Darwinian Evolution ◽  
Hormone Binding ◽  
Exon 2 ◽  
Hormone Homeostasis ◽  
Made In

In larger mammals, thyroid hormone-binding plasma proteins are albumin, transthyretin (TTR) and thyroxine (T4)-binding globulin. They differ characteristically in affinities and release rates for T4 and triiodothyronine (T3). Together, they form a 'buffering' system counteracting thyroid hormone permeation from aqueous to lipid phases. Evolution led to important differences in the expression pattern of these three proteins in tissues. In adult liver, TTR is only made in eutherians and herbivorous marsupials. During development, it is also made in tadpole and fish liver. More intense TTR synthesis than in liver is found in the choroid plexus of reptilians, birds and mammals, but none in the choroid plexus of amphibians and fish, i.e. species without a neocortex. All brain-made TTR is secreted into the cerebrospinal fluid, where it becomes the major thyroid hormone-binding protein. During ontogeny, the maximum TTR synthesis in the choroid plexus precedes that of the growth rate of the brain and occurs during the period of maximum neuroblast replication. TTR is only one component in a network of factors determining thyroid hormone distribution. This explains why, under laboratory conditions, TTR-knockout mice show no major abnormalities. The ratio of TTR affinity for T4 over affinity for T3 is higher in eutherians than in reptiles and birds. This favors T4 transport from blood to brain providing more substrate for conversion of the biologically less active T4 into the biologically more active T3 by the tissue-specific brain deiodinases. The change in affinity of TTR during evolution involves a shortening and an increase in the hydrophilicity of the N-terminal regions of the TTR subunits. The molecular mechanism for this change is a stepwise shift of the splice site at the intron 1/exon 2 border of the TTR gene. The shift probably results from a sequence of single base mutations. Thus, TTR evolution provides an example for a molecular mechanism of positive Darwinian evolution. The amino acid sequences of fish and amphibian TTRs are very similar to those in mammals, suggesting that substantial TTR evolution occurred before the vertebrate stage. Open reading frames for TTR-like sequences already exist in Caenorhabditis elegans, yeast and Escherichia coli genomes.

scholarly journals Thyroid hormone responsiveness in N-Tera-2 cells

2003 ◽  
Vol 178 (1) ◽  
pp. 159-167 ◽  
Author(s):  
S Chan ◽  
CJ McCabe ◽  
TJ Visser ◽  
JA Franklyn ◽  
MD Kilby
Keyword(s):  
Thyroid Hormone ◽  
Mrna Expression ◽  
Hormone Receptors ◽  
Protein A ◽  
Cell Types ◽  
Specific Protein ◽  
Iodothyronine Deiodinases ◽  
Thyroid Hormone Action ◽  
Nt2 Cells ◽  
Free Media

N-TERA-2 cl/D1 (NT2) cells, a human embryonal cell line with characteristics of central nervous system precursor cells, were utilised to study thyroid hormone action during early neuronal growth and differentiation. Undifferentiated NT2 cells expressed mRNAs encoding thyroid hormone receptors (TRs) alpha1, alpha2 and beta1, iodothyronine deiodinases types 2 (D2) and 3 (D3) (which act as the pre-receptor regulators), and the thyroid hormone-responsive genes myelin basic protein (MBP) and neuroendocrine specific protein A (NSP-A). When terminally differentiated into post-mitotic neurons (hNT), TRalpha1 and TRbeta1 mRNA expression was decreased by 74% (P=0.05) and 95% (P<0.0001) respectively, while NSP-A mRNA increased 7-fold (P<0.05). However, mRNAs encoding TRalpha2, D2, D3 and MBP did not alter significantly upon neuronal differentiation and neither did activities of D2 and D3. With increasing 3,5,3'-triiodothyronine (T(3)) concentrations, TRbeta1 mRNA expression in cultured NT2 cells increased 2-fold at 10 nM T(3) and 1.3-fold at 100 nM T(3) (P<0.05) compared with that in T(3)-free media but no change was seen with T(3) treatment of hNT cells. D3 mRNA expression in NT2 cells also increased 3-fold at 10 nM T(3) (P=0.01) and 2.4-fold at 100 nM T(3) (P<0.05) compared with control, but there was no change in D3 enzyme activity. In contrast there was a 20% reduction in D3 mRNA expression in hNT cells at 10 nM T(3) (P<0.05) compared with control, with accompanying reductions in D3 activity with increasing T(3) concentrations (P<0.05). There was no significant change in the expression of the TRalpha isoforms, D2, MBP and NSP-A with increasing T(3) concentrations in either NT2 or hNT cells. Undifferentiated NT2 and differentiated hNT cells show differing patterns of T(3)-responsiveness, suggesting that there are different regulatory factors operating within these cell types.

scholarly journals Local impact of thyroid hormone inactivation

2011 ◽  
Vol 209 (3) ◽  
pp. 273-282 ◽  
Author(s):  
Monica Dentice ◽  
Domenico Salvatore
Keyword(s):  
Thyroid Hormone ◽  
Physiological Function ◽  
Adult Life ◽  
Tissue Expression ◽  
Iodothyronine Deiodinases ◽  
Local Impact ◽  
Hormone Inactivation ◽  
Critical Process ◽  
Made In

Deiodination is a critical process by which the minimally active thyroxine (T4) molecule is converted into the favorite ligand for thyroid hormone (TH) receptors, triiodothyronine (T3). The iodothyronine deiodinases type 1, 2, and 3 (D1, D2, and D3) constitute a potent mechanism of TH activation (D1 and D2) or inactivation (D3), which functions by tissue specifically regulating TH bioavailability. D2 and D3 are widely expressed and in a dynamically and tightly coordinated fashion, thereby allowing cells to customize their own TH activity. D3, the major T3 and T4 inactivating deiodinase, catalyzes their conversion to 3,3′-diiodothyronine and to reverse T3 respectively. According to common wisdom, D3 plays a major role in lowering serum TH concentrations during development, as supported by the much wider D3 tissue expression in the embryo structures than in the adult tissues. However, several recent studies show that D3 is reexpressed in adult life in various pathophysiological contexts, which strengthens the concept that cell-specific TH inactivation is a critical mediator in cellular TH metabolism. This review focuses on the progress made in understanding the physiological function and significance of D3. It summarizes the intriguing evidence that D3 plays a pivotal role in defining local TH concentration in the developing fetus and in several conditions in adult life.

Molecular mechanisms of sex-dependent thyroid hormone action on target tissues

2014 ◽  
Vol 122 (03) ◽  
Author(s):  
H Rakov ◽  
K Engels ◽  
D Zwanziger ◽  
M Renders ◽  
K Brix ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Hormone Action ◽  
Thyroid Hormone Action

Growth hormone treatment in children with idiopathic short stature: correlation of growth response with peripheral thyroid hormone action

2011 ◽  
Vol 74 (3) ◽  
pp. 346-353 ◽  
Author(s):  
Sebastián Susperreguy ◽  
Liliana Muñoz ◽  
Natalia Y. Tkalenko ◽  
Ivan D. Mascanfroni ◽  
Vanina A. Alamino ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Thyroid Hormone ◽  
Short Stature ◽  
Growth Response ◽  
Growth Hormone Treatment ◽  
Hormone Treatment ◽  
Idiopathic Short Stature ◽  
Hormone Action ◽  
Thyroid Hormone Action

scholarly journals Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Fabrice Chatonnet ◽  
Frédéric Picou ◽  
Teddy Fauquier ◽  
Frédéric Flamant
Keyword(s):  
Cerebral Cortex ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Glial Cell ◽  
Nuclear Receptors ◽  
Target Genes ◽  
Cell Types ◽  
Hormone Action ◽  
Cerebral Cortex Development ◽  
Thyroid Hormone Action

Thyroid hormones (TH, including the prohormone thyroxine (T4) and its active deiodinated derivative 3,,5-triiodo-L-thyronine (T3)) are important regulators of vertebrates neurodevelopment. Specific transporters and deiodinases are required to ensure T3 access to the developing brain. T3 activates a number of differentiation processes in neuronal and glial cell types by binding to nuclear receptors, acting directly on transcription. Only few T3 target genes are currently known. Deeper investigations are urgently needed, considering that some chemicals present in food are believed to interfere with T3 signaling with putative neurotoxic consequences.

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