5′-Monodeiodinase activity in developing human cerebral cortex

Karmarkar, M. G.; Prabarkaran, D; Godbole, Madan M.

doi:10.1093/ajcn/57.2.291s

Cited by 49 publications

(26 citation statements)

References 18 publications

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“…The absence of the expected positive signal in the brain mRNA sample could be explained either by very low mRNA levels in this tissue or by a poor representation of D3 expressing portions of the CNS in the sample examined. In addition, D3 activity is much higher in fetal than in adult rat brain (37), and we are aware of only one study demonstrating D3 activity in normal adult human brain (38). D3 activity has been identified in human CNS malignancies (39), and more extensive studies will be required before this issue can be resolved.…”

Section: Discussionmentioning

confidence: 99%

Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme.

Salvatore¹,

Low²,

Berry³

et al. 1995

J. Clin. Invest.

180

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Type 3 iodothyronine deiodinase (D3) catalyzes the conversion of T4 and T3 to inactive metabolites. It is highly expressed in placenta and thus can regulate circulating fetal thyroid hormone concentrations throughout gestation. We have cloned and expressed a 2.1-kb human placental D3 cDNA which encodes a 32-kD protein with a Km of 1.2 nM for 5 deiodination of T3 and 340 nM for 5' deiodination of reverse T3. The reaction requires DTT and is not inhibited by 6n-propylthiouracil. We quantitated transiently expressed D3 by specifically labeling the protein with bromoacetyl [12"'I T3. The KatIK. ratio for 5 deiodination of T3 was over 1,000-fold that for 5' deiodination of reverse T3. Human D3 is a selenoenzyme as evidenced by (a) the presence of an in frame UGA codon at position 144, (b) the synthesis of a 32-kD 75Se-labeled protein in D3 cDNA transfected cells, and (c) the presence of a selenocysteine insertion sequence element in the 3' untranslated region of the mRNA which is required for its expression. The D3 selenocysteine insertion sequence element is more potent than that in the type 1 deiodinase or glutathione peroxidase gene, suggesting a high priority for selenocysteine incorporation into this enzyme. The conservation of this enzyme from Xenopus laevis tadpoles to humans implies an essential role for regulation of thyroid hormone inactivation during embryological development. (J. Clin. Invest. 1995. 96:2421-2430

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Section: Discussionmentioning

confidence: 99%

Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme.

Salvatore¹,

Low²,

Berry³

et al. 1995

J. Clin. Invest.

180

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“…The alteration of specific molecular events probably following the binding of TH to its nuclear receptor, expressed in the cerebral cortex and cerebellum, has been well reported by others and ourselves (Perez-Castillo et al 1985, Karmarkar et al 1993, Mellstorm et al 1991, Chattopadhyay et al 1995, Bradley et al 1994. Ligandbound TH receptor forms a heterodimer with other members of the steroid receptor family and subsequently binds to the thyroid response element of the target gene to alter its expression (Oppenheimer & Schwartz 1997).…”

Section: Introductionmentioning

confidence: 86%

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

Singh¹,

Upadhyay²,

Kumar³

et al. 2003

Journal of Endocrinology

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Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-x L and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-x L were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by downregulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.

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“…TH is known to regulate gene expression by binding to its nuclear receptors, expressed in different parts of the brain from early to adult stages (Bernal & Pekonen 1984, Perez-Castillo et al 1985, Strait et al 1991, Bradley et al 1992, Karmarkar et al 1993, Chattopadhyay et al 1995. The influence of TH on known target genes, namely RC3, MBP, MAP and PCP-2, has been demonstrated but has not increased our understanding of brain development (Silva & Rudas 1990, Farsetti et al 1991, Iniguez et al 1993, Zou et al 1994.…”

Section: Introductionmentioning

confidence: 99%

Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development

Singh

Upadhyay²,

Godbole

2003

Journal of Endocrinology

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Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.

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5′-Monodeiodinase activity in developing human cerebral cortex

Cited by 49 publications

References 18 publications

Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme.

Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme.

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development

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