The human, but not rat, dio2 gene is stimulated by thyroid transcription factor-1 (TTF-1)
Open accessAbstract
Types 1 and 2 iodothyronine deiodinases (D1 and D2) catalyze the production of T(3) from T(4). D2 mRNA is abundant in the human thyroid but very low in adult rat thyroid, whereas D1 activity is high in both. To understand the molecular regulation of these genes in thyroid cells, the effect of thyroid transcription factor 1 (TTF-1) and the paired domain-containing protein 8 (Pax-8) on the transcriptional activity of the deiodinase promoters were studied. Both the approximately 6.5-kb hdio2 sequence and its most 3' 633 bp were activated 10-fold by transiently expressed TTF-1 in COS-7 cells, but the hdio1 was unaffected. Surprisingly, the response of the rdio2 gene to TTF-1 was only 3-fold despite the 73% identity with the proximal 633-bp region of hdio2 including complete conservation of a functional cAMP response element at -90. Neither human nor rat dio2 nor human dio1 was induced by Pax-8. The binding affinity of four putative TTF-1 binding sites in hdio2 were compared by a semiquantitative gel retardation assay using in vitro expressed TTF-1 homeodomain protein. Only two sites, D and C1 (both of which are absent in rdio2), had significant affinity. Functional analyses showed that both sites are required for the full response to TTF-1. These results can explain the differential expression of dio2 in thyroid and potentially other tissues in humans and rats.
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The DIO2 promoter contains both a CREB-binding site and a TTF1 binding site, and TSH and TTF1 upregulate DIO2 activity.
“The promoter of the DIO2 gene contains both CREB-binding site and TTF1 binding site, and TSH and TTF1 were shown to upregulate DIO2 activity ( Figure 3F ) (176, 177).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [177]
The Discussion reports a functional CRE and TTF-1 binding sites in the human DIO2 promoter, and the promoter-response results show that TTF-1 increases its transcriptional activity. The paper does not show that TSH upregulates DIO2 activity; its rat-thyroid results instead report lower D2 mRNA after TSH stimulation. (LLM, conf=0.88)
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Devriendt, K., Vanhole, C., Matthijs, G., & de Zegher, F. (1998) · New England Journal of Medicine · doi:10.1056/nejm199804303381817 · Cited by 263 · see citing works
Type 2 iodothyronine deiodinase is highly expressed in human thyroid.
Salvatore, D., Tu, H., Harney, J. W., & Larsen, P. R. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118880 · Cited by 196 · see citing works
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Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.1.0455 · Cited by 1,853 · see citing works
Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1
Gereben, B., Zavacki, A. M., Ribich, S., Kim, B. W., Huang, S. A., Simonides, W. S., Zeöld, A., & Bianco, A. C. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0019 · Cited by 891 · see citing works
Self-citationGereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7396-0 · Cited by 207 · see citing works
Self-citationFekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1439 · Cited by 179 · see citing works
Self-citationCharacterization of the Nuclear Factor-κB Responsiveness of the Human dio2 Gene
Zeöld, A., Doleschall, M., Haffner, M. C., Capelo, L. P., Menyhért, J., Liposits, Z., da Silva, W. S., Bianco, A. C., Kacskovics, I., Fekete, C., et al. (2006) · Endocrinology · doi:10.1210/en.2005-1608 · Cited by 72 · see citing works
Self-citationIntrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61 · see citing works
Regulation of Tissue Iodothyronine Deiodinase Activity in a Model of Prolonged Critical Illness
Debaveye, Y., Ellger, B., Mebis, L., Darras, V. M., & Van den Berghe, G. (2008) · Thyroid · doi:10.1089/thy.2007.0287 · Cited by 50 · see citing works
- Authors
- Gereben, B., Salvatore, D., Harney, J. W., Tu, H. M., & Larsen, P. R.
- Affiliations
- Thyroid Division (B.G., J.W.H., H.M.T., P.R.L.) Department of Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 02115
- University of Naples Federico II (IT)
- Brigham and Women's Hospital (US)
- Corresponding author
- Larsen, P. Reed
- ORCID
- Salvatore, Domenico
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2001-01-01
- Volume
- 15
- Issue
- 1
- Pages
- 112-124
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W1979495452
- Cited by
- 70
- References
- 2
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 2 · 2012: 5
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK36256, R01DK036256, T32DK007529)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TTF-1, PAX8, transcriptional regulation, thyroid-specific gene expression, cAMP response element, thyroid hormone activation
- MeSH terms
- PAX8 Transcription Factor, Thyroid Nuclear Factor 1, Animals, Base Sequence, Binding Sites, Cell Line, DNA, DNA-Binding Proteins, Humans, Iodide Peroxidase, Iodine Radioisotopes, Kinetics, Male, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Propylthiouracil, RNA, Messenger, Species Specificity, Thyroid Gland, Thyroxine, Transcription Factors, Transcription, Genetic, Trans-Activators, Gene Library, Gene Expression, Rats, Sprague-Dawley, Sequence Homology, Cyclic AMP-Dependent Protein Kinases, Rats, Paired Box Transcription Factors
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