Pre-Translational and Post-Translational Regulation of TSH Synthesis in Normal and Neoplastic Thyrotrophs

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-β 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-β gene fused to the chloramphenicol acetyltransferase gene. The first exon of human TSH-β, contains an element that increases basal expression and mediates T₃-induced gene repression, probably through a direct interaction with c-erbAβ. This transcriptional repression by T₃ appears aberrant in thyrotropic tumors. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-β 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.