Transcriptional control of the forkhead thyroid transcription factor TTF-2 by thyrotropin, insulin, and insulin-like growth factor I
Open accessAbstract
The hormonal regulation of both thyroglobulin and thyroperoxidase promoter activity in FRTL-5 thyroid cells takes place, at least in part, through a hormone-responsive element to which the thyroid transcription factor TTF-2 binds. The TTF-2 cDNA, encoded by the titf2 locus, has recently been cloned and classified as a member of the forkhead transcription factor family. Here, we demonstrate that TTF-2 mRNA levels become undetectable in FRTL-5 thyroid cells cultured for 4 days in 0.2% serum and in the absent of thyrotropin (TSH) and insulin. Addition of TSH, insulin or insulin-like growth factor I (IGF-I) to the culture medium increases the levels of this transcription factor in a dose- and time- dependent manner and requires ongoing protein synthesis. The TSH effect is greater than that produced by insulin or IGF-I and is similar to the effect produced by the cAMP analog forskolin. The TSH and insulin effects are additive. In all cases, the mRNA levels increase is accompanied by an increase in transcription rate, as demonstrated by run-off assays. These data demonstrate that the TTF-2 mRNA is under tight hormonal control. This is consistent with an important role for TTF-2 as a mediator of the transcriptional activation of thyroid-specific genes (thyroglobulin and thyroperoxidase) by TSH via cAMP and by insulin through the IGF-I receptor.
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In FRTL-5 cells, TSH-stimulated upregulation of TTF2 mRNA levels appears to be mediated by the cAMP/PKA/CREB pathway.
“in FRTL-5 cells it was found that TSH-stimulated upregulation of TTF2 mRNA levels appears to be mediated by the cAMP/PKA/CREB pathway (154).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [154]
The Results report that TSH increases TTF-2 mRNA in FRTL-5 cells and that forskolin produces a similar effect; the Discussion says this suggests TSH acts through the cAMP pathway (page numbers unavailable in our copy). The paper does not establish the additional PKA/CREB steps and says further work is needed to determine how TSH regulates TTF-2. (LLM, conf=0.88)
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Research works printed but not linked: 7
- Taurog, A. (1976) in The Thyroid: A Fundamental and Clinical Text (Braverman, L. E., and Utiger, R. D., eds) pp. 47-81, Lippincott-Raven, New York
- Salvatore, G., Stambury, J. B., and Rall, J. E. (1980) in The Thyroid Gland (De Visscher, M., ed) pp. 443-487, Raven Press, New York
- Van Heuverswyn, G., Streydio, C., Brocas, H., Refetoff, S., Dumont, J., and Vassart G. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 5941-5945
- Lai, E., Clark, K. L., Burley, S. K., and Darnell, J. E., Jr. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 10421-10423
- Ambesi-Impiombato, F. S., Parks, L. A. M., and Coo, H. G. (1980) Proc. Natl. Acad. Sci. U. S. A. 77, 3455-3459
- Alexander, M. C., Lomanto, M., Nasrin, N., and Ramaika, C. (1988) Proc. Natl. Acad. Sci. U. S. A. 87, 5273-5277
- Montminy, M. R., Sevario, K. A., Wagner, J. A., Mandel, G., and Goodman, R. H. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 6682-6686
Cited by
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Thyroid transcription factors in development, differentiation and disease
Fernández, L. P., López-Márquez, A., & Santisteban, P. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.186 · Cited by 258 · 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
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
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- Authors
- Ortiz, L., Zannini, M., Di Lauro, R., & Santisteban, P.
- Affiliations
- University of Naples Federico II (IT)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Santisteban, Pilar
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-09
- Volume
- 272
- Issue
- 37
- Pages
- 23334-23339
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2063393711
- Cited by
- 73
- References
- 0
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 1
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Funders
- Consiglio Nazionale delle Ricerche
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- forkhead transcription factor, thyroid transcription factors, thyroid-stimulating hormone, insulin, insulin-like growth factor I, thyroglobulin promoter, hormone response elements, FRTL-5 cells, cAMP signaling, forskolin, IGF-1 receptor, transcriptional regulation
- MeSH terms
- Cyclic AMP, DNA-Binding Proteins, Dose-Response Relationship, Drug, Colforsin, Gene Expression Regulation, Glyceraldehyde-3-Phosphate Dehydrogenases, Insulin, Insulin-Like Growth Factor I, Iodide Peroxidase, Nuclear Proteins, Repressor Proteins, RNA, Messenger, Thyroglobulin, Thyroid Gland, Thyrotropin, Transcription Factors, Transcription, Genetic, Signal Transduction, Forkhead Transcription Factors
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