Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

Physiological and molecular basis of thyroid hormone action.

Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear receptors (TRs) mediate the biological activities of T3 via transcriptional regulation. Two TR genes, α and β, encode four T3-binding receptor isoforms (α1, β1, β2, and β3). The transcriptional activity of TRs is regulated at multiple levels. Besides being regulated by T3, transcriptional activity is regulated by the type of thyroid hormone response elements located on the promoters of T3 target genes, by the developmental- and tissue-dependent expression of TR isoforms, and by a host of nuclear coregulatory proteins. These nuclear coregulatory proteins modulate the transcription activity of TRs in a T3-dependent manner. In the absence of T3, corepressors act to repress the basal transcriptional activity, whereas in the presence of T3, coactivators function to activate transcription. The critical role of TRs is evident in that mutations of th...

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Molecular aspects of thyroid hormone actions.

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.

Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis- Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tenta...

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Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability

A cDNA clone encoding a human cytosolic thyroid hormone-binding protein (p58) has been isolated. The human sequence was found to be homologous to that of rat pyruvate kinase (EC 2.7.1.40) subtype M2. p58 is a monomer that has approximately 5% the enzymatic activity of the tetrameric pyruvate kinase M2. The tetrameric M2 does not bind 3,3',5-triiodo-L-thyronine (T3). Binding of p58 to T3 and its analogs resulted in the inhibition of its pyruvate kinase activity. The apparent Ki values of T3, L-thyroxine, and D-T3 are 30 nM, 100 nM, and 2 mM, respectively. L-Thyronine and 3,3',5'-triiodo-L-thyronine had no effect. This order of activity correlates with the thermogenic effects reported for T3 and its analogs. Conversion of p58 to the tetramer is reversible and is under the control of fructose 1,6-bisphosphate. The conversion is inhibited by T3 in a dose-dependent manner. Since pyruvate kinase is a key enzyme in regulating cellular ADP, ATP, and pyruvate, our findings suggest that p58 may be involved in mediating some of the cellular metabolic effects induced by thyroid hormones.

https://www.pnas.org/content/pnas/86/20/7861.full.pdf

Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase.

Regulation of thyroid hormone binding to its cytosolic binding protein by L-α-alanine

High level expression of p55, a thyroid hormone binding protein which is homologous to protein disulfide isomerase in a retroviral vector

Pyruvate kinase (PK), a cytosolic enzyme, catalyzes the conversion of phosphoenolpyruvate' to pyruvate with the generation of ATP. We have isolated a full length cDNA clone from a Xgtll cDNA library constructed from rat pituitary GH3 cells by using a 475 bp Pstl fragment from a human PK cDNA (1). The sequence is 2310 bp long and contains a long open reading frame of 1593 bp with an initiation codon at nucleotide position 90 and a termination codon at 1683. The open reading frame encodes a protein of 531 amino acids with a calculated molecular weight of 57,978. It consists of a 84-bp 5'-untranslated and 296-bp 3'-untranslated region. The sequence is highly homologous to the rat liver pyruvate kinase subtype Mj (2), having a 991 sequence similarity at the amino acid level.

Hirokazu Kato

Papers

Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase.

Regulation of thyroid hormone binding to its cytosolic binding protein by L-α-alanine

High level expression of p55, a thyroid hormone binding protein which is homologous to protein disulfide isomerase in a retroviral vector

The nucleotide sequence of a full length cDNA encoding rat pituitary pyruvate kinase.