Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues.

Abstract

The deiodination of thyroid hormones in extrathyroidal tissues plays an important role in modulating thyroid hormone action. The type II deiodinase (DII) converts thyroxine to the active hormone 3,5,3 Ј -triiodothyronine, and in the rat is expressed in the brain, pituitary gland, and brown adipose tissue (BAT). Complementary DNAs (cDNAs) for the types I and III deiodinases (DI and DIII, respectively) have been isolated and shown to code for selenoproteins. However, information concerning the structure of the mammalian DII remains limited, and the pattern of its expression in human tissues is undefined. We report herein the identification and characterization of rat and human DII cDNAs. Both code for selenoproteins and exhibit limited regions of homology with the DI and DIII. In the rat pituitary and BAT, DII mRNA levels are altered more than 10-fold by changes in the thyroid hormone status of the animal. Northern analysis of RNA derived from human tissues reveals expression of DII transcripts in heart, skeletal muscle, placenta, fetal brain, and several regions of the adult brain. These studies demonstrate that: ( a ) the rat and human DII are selenoproteins, ( b ) DII expression in the rat is regulated, at least in part, at the pretranslational level in some tissues, and ( c ) DII is likely to be of considerable physiologic importance in thyroid hormone economy in the human fetus and adult. ( J. Clin. Invest. 1996. 98:405-417.)

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

“…These observations demonstrate that the benefit of D2 overexpression after pressure overload does not simply originate from enhanced contractile function seen with D2 overexpression in nonbanded hearts. Discussion D2 converts the prohormone TH, T4, to active T3 (16,17) and is the primary source of T3 in many tissues of the body, such as brain and human heart. Because altered TH signaling or metabolism is postulated to occur in heart disease (5, 7, 8) and because TH has been advocated as cardiac disease treatment (12), we created mice conditionally expressing D2 in the heart (18).…”

“…Type 2 deiodinase (D2) is a conserved 5Ј deiodinase enzyme that is expressed in human myocardium, where it converts prohormone T4 into active T3 (16,17). We created transgenic mice that conditionally overexpress D2 in the heart.…”

The Human Type 2 Iodothyronine Deiodinase Is a Selenoprotein Highly Expressed in a Mesothelioma Cell Line

“…The most recently cloned deiodinase is the type 2 (D2), a propylthiouracil (PTU)-resistant, low K m (T 4 ) obligate outer ring deiodinase that catalyzes T 4 to T 3 conversion (4,5). The major open reading frame of the hD2 cDNA encodes a putative ϳ31-kDa protein with high similarity of the Sec-containing active center of the putative D2 enzyme with those of D1 and the other member of this group, type 3 iodothyronine deiodinase (D3) (6).…”

“…Three major arguments support this position, namely 1) the failure of Se deficiency to reduce D2 catalytic activity either in vivo or in vitro (9,15,16), 2) the inability to identify a 75 Se-labeled protein of the expected size in cells expressing D2 (13), and 3) the inability to identify immunoreactive protein by Western analysis, immunoprecipitation (IP), or immunocytochemistry using antibodies prepared against peptides deduced from the sequence of the putative D2 mRNA (4). An alternative scenario put forward is that D2 is a large protein complex (200 kDa) containing one or more 29-kDa substrate-binding subunits (p29), an ϳ60-kDa cAMP-induced activation protein, and one or more catalytic subunits (12).…”

Selenocysteine-containing proteins in mammals

“…It should also be noted that an excellent review on the deiodinase family has recently been published [62] and a more detailed account of the substrates, substrate specificities and primary structures of each deiodinase may be found in this review. Interestingly, a second TGA codon is encoded in the gene for rat and human D2 eight codons from the termination codon that may signal Sec insertion into protein or termination of protein synthesis during transient expression [24,85]. D2 is expressed in the pituitary gland, the central nervous system, placenta and brown fat of humans and rats and in the thyroid gland and skeletal and heart muscle of humans, but not rats.…”