Interleukin-1β modulates endogenous thyroid hormone receptor α gene transcription in liver cells

One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum triiodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease D1 and thyroid hormone receptor (TR)β1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)κB and activator protein (AP)-1. The proinflammatory cytokine interleukin (IL)-1β decreases thyroid hormone receptor (TR)β1 mRNA in an NFκB-dependent way. The aim of this study was to unravel the effects of IL-1β on endogenous TRα gene expression in an animal model and in a liver cell line. The TRα gene product is alternatively spliced in TRα1 and TRα2, TRα2 is capable of inhibiting TRα1-induced gene transcription. We showed that both TRα1 and TRα2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1β stimulation of hepatoma cells (HepG2). Using the NFκB inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1β-induced decrease in TRα mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NFκB and AP-1. The IL-1β-induced TRα1 and TRα2 mRNA decrease in HepG2 cells is the result of decreased TRα gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of de novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization.

Download Full-text

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

Journal of Molecular Endocrinology ◽

10.1677/jme-08-0023 ◽

2008 ◽

Vol 41 (1) ◽

pp. 25-34 ◽

Cited By ~ 6

Author(s):

Anne Wulf ◽

Marianne G Wetzel ◽

Maxim Kebenko ◽

Meike Kröger ◽

Angelika Harneit ◽

...

Keyword(s):

Thyroid Hormone ◽

Dna Binding ◽

Gene Transcription ◽

Hormone Receptor ◽

Target Genes ◽

Thyroid Hormone Receptor ◽

Point Mutations ◽

Chimeric Protein ◽

Functional Consequences ◽

Glycerol 3 Phosphate Dehydrogenase

Thyroid hormone 3,3′,5-tri-iodothyronine (T3) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T3-regulated target gene (TSHα). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T3. T3-mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T3-regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.

Download Full-text

Interactions of Thyroid Hormone Receptor with Ku Proteins and Interleukin Enhancer Binding Factor 3 Modulate the Promoter Activity of Thyroid-Stimulating Hormone Alpha

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.35.380 ◽

2012 ◽

Vol 35 (3) ◽

pp. 380-384 ◽

Cited By ~ 1

Author(s):

Masae Ohno ◽

Mayu Fujita ◽

Makoto Nishizuka ◽

Shigehiro Osada ◽

Masayoshi Imagawa

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Promoter Activity ◽

Thyroid Hormone Receptor ◽

Thyroid Stimulating Hormone ◽

Binding Factor ◽

Ku Proteins ◽

Stimulating Hormone

Download Full-text

Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells

Oncogene ◽

10.1038/onc.2013.309 ◽

2013 ◽

Vol 32 (38) ◽

pp. 4509-4518 ◽

Cited By ~ 25

Author(s):

Y-H Lin ◽

C-J Liao ◽

Y-H Huang ◽

M-H Wu ◽

H-C Chi ◽

...

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Tumor Metastasis ◽

Thyroid Hormone Receptor ◽

Hepatoma Cells ◽

Human Hepatoma ◽

Human Hepatoma Cells

Download Full-text

Thyroid hormone receptor α isoforms generated by alternative splicing differentially activate myosin HC gene transcription

Nature ◽

10.1038/334539a0 ◽

1988 ◽

Vol 334 (6182) ◽

pp. 539-542 ◽

Cited By ~ 261

Author(s):

Seigo Izumo ◽

Vijak Mahdavi

Keyword(s):

Alternative Splicing ◽

Thyroid Hormone ◽

Gene Transcription ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Thyroid Hormone Receptor Α

Download Full-text

Ligand-dependent enhancement of human antithrombin gene expression by retinoid X receptor α and thyroid hormone receptor β

Biochemical Journal ◽

10.1042/bj3180263 ◽

1996 ◽

Vol 318 (1) ◽

pp. 263-270 ◽

Cited By ~ 6

Author(s):

René W. L. M. NIESSEN ◽

Farhad REZAEE ◽

Pieter H. REITSMA ◽

Marjolein PETERS ◽

Jan J. M. de VIJLDER ◽

...

Keyword(s):

Gene Expression ◽

Thyroid Hormone ◽

Hormone Receptor ◽

Promoter Region ◽

Promoter Activity ◽

Thyroid Hormone Receptor ◽

Retinoid X Receptor ◽

Hepatoma Cell Line ◽

Promoter Fragment ◽

Thyroid Hormone Receptor Β

We studied potential modulators of antithrombin gene expression. A putative hormone response element (HRE) was identified by sequence similarity analysis of the antithrombin promoter, situated between nucleotides -92 and -54 relative to the transcription start site. This HRE contains three hexanucleotide motifs with an AGGTCA consensus, which are potential targets of members of the steroid/thyroid superfamily of nuclear receptors. Stimulation of the hepatoma cell line HepG2 with the receptor ligands l-3,5,3´-tri-iodothyronine, all-trans retinoic acid, or their combination, increased production of antithrombin into the culture medium by 1.3-, 1.6-, and 2.0-fold, respectively. In contrast, the receptor ligand 1,25-dihydroxycholecalciferol [1,25-(OH)2VitD3] did not influence antithrombin production. Analysis of promoter chloramphenicol acetyltransferase (CAT) constructs, showed that the first 86 bp of the antithrombin promoter region are sufficient for basal transcription. The DNA length polymorphism of 32 bp or 108 bp, located upstream of position -276, did not influence antithrombin promoter activity. The antithrombin promoter activity dropped to background values when deleting the region -97/-49 of promoter fragment -453/+57. Transactivation of the antithrombin promoter by retinoid X receptor α (RXRα) (5–7-fold) or thyroid hormone receptor β (TRβ) (4–5-fold) was only observed when at least -167/+57 bp of the promoter region is present in CAT constructs, and when the appropriate ligand of the nuclear receptor was added. This transactivation was not observed upon deletion of the antithrombin promoter region -97/-49. With three copies of the antithrombin promoter fragment -109/-42 in front of the thymidine kinase minimal promoter, transactivation was only obtained with RXRα, and not with TRβ. In conclusion, these results indicate that the ligand-dependent enhancement of antithrombin gene expression is regulated by RXRα as well as by TRβ. Transactivation of antithrombin gene expression by RXRα and TRβ appears to be dependent upon the presence of promoter region up to nucleotide -167. The HRE segment (-109/-42) only confers RXRα responsiveness to a heterologous promoter. Further study is needed to unravel the exact nature of this HRE and its 5´-flanking sequences.

Download Full-text