Expression and function of the homeodomain-containing protein hex in thyroid cells
Open accessAbstract
The homeodomain-containing protein Hex (also named Prh) is expressed in primitive endoderm (during the early phases of development), in some endoderm-derived tissues and in endothelial and hematopoietic precursors. Hex expression is exting-uished during terminal differentiation of endothelial and hematopoietic cells as well as in adult lung. Previous investigations have demonstrated that Hex is expressed during early thyroid gland development. No information has been reported on Hex expression in adult thyroid gland or on the function of this protein in follicular thyroid cells. These issues represent the focus of the present study. We demonstrate that Hex mRNA is present in rat and human adult thyroid gland as well as in differentiated follicular thyroid cell lines. In FRTL-5 cells TSH reduces Hex expression. In thyroid cell lines transformed by several oncogenes Hex expression is completely abolished. By using co-transfection assays we demonstrate that Hex is a repressor of the thyroglobulin promoter and that it is able to abolish the activating effects of both TTF-1 and Pax8. These data would suggest that Hex may play an important role in thyroid cell differentiation. Protein-DNA interaction experiments indicate that Hex is able to bind sites of the thyroglobulin promoter containing either the core sequence 5'-TAAT-3' or 5'-CAAG-3'. The DNA binding specificity of the Hex homeodomain, therefore, is more 'relaxed' than that observed in the majority of other homeo-domains.
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TSH binding to TSHR activates signal transduction pathways that regulate TTF activities, which in turn control expression of thyroid-specific functional proteins including NIS, pendrin, TG, TPO, DUOX(A)1/2, DIO1 and DIO2, participating in TH synthesis and secretion.
“Binding of TSH to TSHR activates signal transduction pathways that regulate TTF activities, which in turn control the gene expression of many thyroid-specific functional proteins, including NIS, pendrin, TG, TPO, DUOX(A)1/2, DIO1 and DIO2, that participate in the synthesis and secretion of THs (158, 159).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [159]
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Experimental — accuracy not yet measuredHHEX binds to the TG promoter and functions as a repressor to abolish the activating effects of both TTF1 and PAX8 in FRTL-5 cells.
“HHEX can bind to the TG promoter and function as a repressor to abolish the activating effects of both TTF1 and PAX8 in FRTL-5 cells (159).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [159]
The Results (p. 2506) report that Hex abolishes both TTF-1 and Pax8 activation of the Tg promoter, and the Discussion describes Hex as a Tg-promoter repressor. But the Methods place the TTF-1/Pax8 co-transfection experiments in HeLa cells; the FRTL-5 experiment tested Hex-mediated repression, not abolition of both factors’ activating effects. The binding assays used Tg-promoter sequences (Fig. 6, p. 2509). (LLM, conf=0.93)
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Transcriptional activation by recruitment
Ptashne, M., & Gann, A. (1997) · Nature · doi:10.1038/386569a0 · Cited by 1,158 · see citing works
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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
Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex
Foley, A. C., & Mercola, M. (2005) · Genes & Development · doi:10.1101/gad.1279405 · Cited by 195 · see citing works
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
- Authors
- Pellizzari, L., D'Elia, A., Rustighi, A., Manfioletti, G., Tell, G., & Damante, G.
- Affiliations
- University of Udine (IT)
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-07-01
- Volume
- 28
- Issue
- 13
- Pages
- 2503-2511
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC102703
- OpenAlex
- W2154697123
- Cited by
- 68
- References
- 1
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 3 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nucleic Acids Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Funders
- Consiglio Nazionale delle Ricerche
- Centre National de la Recherche Scientifique
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- Hex, homeodomain transcription factor, thyroid gland, thyroglobulin promoter, transcriptional repression, thyroid-stimulating hormone, TTF-1, PAX8, thyroid cell differentiation, oncogenic transformation, DNA binding specificity, FRTL-5 cells
- MeSH terms
- PAX8 Transcription Factor, Thyroid Nuclear Factor 1, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, Cell Transformation, Neoplastic, DNA, DNA-Binding Proteins, Gene Expression Regulation, Humans, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Repressor Proteins, RNA, Messenger, Substrate Specificity, Thyroglobulin, Thyroid Gland, Thyrotropin, Transcription Factors, Transcription, Genetic, Transfection, Trans-Activators, Sequence Alignment, Homeodomain Proteins, Mice, Rats, Paired Box Transcription Factors
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