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Pre-translational and post-translational regulation of TSH synthesis in normal and neoplastic thyrotrophs
B D Weintraub1, F E Wondisford, E A Farr
1NIDDK, National Institutes of Health, Bethesda, Md.
Abstract:
We are interested in the mechanisms by which endocrine and developmental factors regulate TSH synthesis at both pre-translational and post-translational levels. Thyroid hormone profoundly decreases transcription of the TSH-beta gene, while TRH and agents modifying cyclic AMP increase transcription. To elucidate the molecular mechanisms underlying these effects, human embryonal kidney cells were transfected with constructs of the human TSH-beta gene fused to the chloramphenicol acetyltransferase gene. The first exon of human TSH-beta, contains an element that increases basal expression and mediates T3-induced gene repression, probably through a direct interaction with c-erbA beta. This transcriptional repression by T3 appears aberrant in thyrotropic tumors. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-beta through interacting with upstream regulatory elements. Thyroid hormone, TRH and developmental factors also regulate the branching pattern and relative sialylation of TSH carbohydrate chains, which may affect TSH action in vitro and in vivo. Certain thyrotropic tumors produce TSH with more complex carbohydrate branching patterns, which may increase its biologic activity.
Insights
Thyroid hormone and TRH regulate TSH-beta gene transcription and TSH carbohydrate structure. Aberrant TSH regulation occurs in thyrotropic tumors, potentially increasing biologic activity.
Area of Science:
- Endocrinology
- Molecular Biology
- Gene Regulation
Background:
- Thyroid-stimulating hormone (TSH) synthesis is regulated by endocrine and developmental factors.
- Thyroid hormone (T3) suppresses TSH-beta gene transcription, while thyrotropin-releasing hormone (TRH) and cyclic AMP (cAMP) increase it.
Purpose of the Study:
- To elucidate the molecular mechanisms of TSH-beta gene regulation by T3 and TRH.
- To investigate the role of developmental factors in TSH glycosylation and its impact on TSH action.
Main Methods:
- Transfection of human embryonal kidney cells with human TSH-beta gene constructs linked to a reporter gene.
- Analysis of gene transcription regulation and carbohydrate chain modifications.
Main Results:
- A regulatory element in the first exon of the TSH-beta gene mediates T3-induced repression, potentially via c-erbA beta interaction.
- This T3-mediated repression is aberrant in thyrotropic tumors.
- TRH and cAMP-elevating agents increase TSH-beta transcription through upstream elements.
- Hormonal and developmental factors influence TSH carbohydrate branching and sialylation.
Conclusions:
- TSH-beta gene transcription is precisely controlled by thyroid hormone and TRH through distinct regulatory mechanisms.
- Aberrant TSH regulation in tumors may lead to altered TSH bioactivity.
- Post-translational modifications, specifically carbohydrate structure, play a role in TSH function and may be altered in disease states.