Thyrotropin regulation of differentiated gene transcription in adult human thyrocytes in primary culture
Open accessAbstract
Thyroid transcription factors (TTFs) - NKX2-1, FOXE1, PAX8 and HHEX - regulate multiple genes involved in thyroid development in mice but little is known about TTF regulation of thyroid-specific genes - thyroglobulin (TG), thyroid peroxidase (TPO), deiodinase type 2 (DIO2), sodium/iodide symporter (NIS) and TSH receptor (TSHR) - in adult, human thyrocytes. Thyrotropin (thyroid-stimulating hormone, TSH) regulation of thyroid-specific gene expression in primary cultures of human thyrocytes is biphasic yielding an inverted U-shaped dose-response curve (IUDRC) with upregulation at low doses and decreases at high doses. Herein we show that NKX2-1, FOXE1 and PAX8 are required for TSH-induced upregulation of the mRNA levels of TG, TPO, DIO2, NIS, and TSHR whereas HHEX has little effect on the levels of these thyroid-specific gene mRNAs. We show that TSH-induced upregulation is mediated by changes in their transcription and not by changes in the degradation of their mRNAs. In contrast to the IUDRC of thyroid-specific genes, TSH effects on the levels of the mRNAs for NKX2-1, FOXE1 and PAX8 exhibit monophasic decreases at high doses of TSH whereas TSH regulation of HHEX mRNA levels exhibits an IUDRC that overlaps the IUDRC of thyroid-specific genes. In contrast to findings during mouse development, TTFs do not have major effects on the levels of other TTF mRNAs in adult, human thyrocytes. Thus, we found similarities and important differences in the regulation of thyroid-specific genes in mouse development and TSH regulation of these genes in adult, human thyrocytes.
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In primary human thyrocytes, TSH induces a bell-shaped dose-response of HHEX, TG, NIS, TPO, DIO2, and TSHR mRNA expression and secreted TG protein, with peak response at about 10 mU/mL.
“In primary human thyrocytes, TSH induced bell-shaped dose-response of HHEX, TG, NIS, TPO, DIO2, and TSHR mRNA expression and secreted TG protein (163, 198). The TSH concentration associated with the peak response is about 10 mU/mL.”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [163]
The Results and Discussion report inverted U-shaped TSH responses for HHEX, TG, NIS, TPO, DIO2, and TSHR mRNAs in primary human thyrocytes (page not provided). The Results mention increased TG protein in previous reports, but do not establish a bell-shaped response for secreted TG protein. The Methods use 10 mU/mL TSH for a TPO protein experiment; they do not identify it as the peak dose for the claimed responses. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn primary human thyrocytes, knockdown of TTF1, TTF2, PAX8 but not HHEX markedly inhibits TSH-stimulated NIS mRNA expression.
“In primary human thyrocytes, knockdown of TTF1, TTF2, PAX8 but not HHEX genes markedly inhibited TSH-stimulated NIS mRNA expression (163).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [163]
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Sorted by citations
Intrathyroidal 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
López-Márquez, A., Carrasco-López, C., Fernández-Méndez, C., & Santisteban, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.654569 · Cited by 49 · see citing works
- Authors
- Jang, D., Marcus-Samuels, B., Morgan, S. J., Klubo-Gwiezdzinska, J., Neumann, S., & Gershengorn, M. C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gershengorn, Marvin C.
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 518
- Pages
- 111032
- ISSN
- 0303-7207 (ISSN-L)
- PMC
- PMC7606794
- OpenAlex
- W3086981293
- Cited by
- 22
- References
- 2
- Citations by year
- 2026: 3 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 2
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- 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
- thyroid-stimulating hormone, thyroid transcription factors, TTF-1, FOXE1, PAX8, HHEX, thyroid follicular cells, thyroglobulin, thyroid peroxidase, type 2 deiodinase, sodium iodide symporter, TSH receptor, thyroid-specific gene expression, mRNA stability, thyroid development
- MeSH terms
- PAX8 Transcription Factor, Thyroid Epithelial Cells, Thyroid Nuclear Factor 1, Iodothyronine Deiodinase Type II, Adult, Autoantigens, Cell Differentiation, Cells, Cultured, Humans, Iodide Peroxidase, Organ Specificity, Receptors, Thyrotropin, Thyroglobulin, Thyrotropin, Transcription, Genetic, RNA Stability, Iron-Binding Proteins, Primary Cell Culture
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