Control of Thyroperoxidase and Thyroglobulin Transcription by cAMP: Evidence for Distinct Regulatory Mechanisms

Abstract

The expression of the genes coding for thyroglobulin (TG), and thyroperoxidase (TPO), are regulated by TSH. These effects are mediated by cAMP as they are reproduced by forskolin. In vitro run-on transcription assays performed on nuclei isolated from dog thyrocytes in culture or from dog thyroid slices, indicate that the forskolin-induced transcriptional stimulation of TG and TPO genes are very different. For the TG gene, the kinetics of transcriptional activation vary according to the experimental model: it is rapid (1 h) in thyroid slices and slow (8 h) in primary cultures. In contrast, TPO induction is rapid in both cases. In primary cultures, insulin is responsible for the basal level and for a part of forskolin-induced TG transcription, whereas TPO transcription is not affected by insulin. The forskolin-induced increase of TG transcription requires ongoing protein synthesis, as it is blocked by cycloheximide. TPO gene transcription is unaffected by cycloheximide. Taken together with previous data on the two genes, our results suggest that while TPO regulation corresponds to the classical model of genes in which the promoter is regulated directly via cAMP regulatory elements, TG gene regulation involves the synthesis of an intermediary, rapid turnover trans-acting protein.

Cyclin D3 accumulation and activity integrate and rank the comitogenic pathways of thyrotropin and insulin in thyrocytes in primary culture

“…A total of 370 cells were injected in each condition 1995Dremier et al, 1997). In this system, other TSH responses including cAMP accumulation, iodide uptake, thyroperoxidase expression, the synthesis of various proteins separated by two-dimensional gel electrophoresis, and transient c-myc expression are independent of insulin (Lamy et al, 1989;Deleu et al, 1999a;Gerard et al, 1989). On the other hand, various insulin/IGF-1 actions including PKB activation (Coulonval et al, submitted), the expression of several immediate/early protooncogenes (Deleu et al, 1999a), and the stimulation of overall RNA and protein syntheses (Deleu et al, 1999b) are independent of TSH at least during a ®rst 16-h period.…”

The dog thyroid primary culture system: a model of the regulation of function, growth and differentiation expression by cAMP and other well-defined signaling cascades

“…In both cases, transcription is detectable at 1 h after stimulation (25,69). This indicates that the pathways used to regulate the transcriptional activity of Tg and TPO genes differ at some step(s) downstream from the generation of the cAMP signal.…”

“…The basal expression of Tg gene (but not its stimulation by TSH) is strictly dependent on the presence of insulin in the culture medium (68,69), but insulin does not affect TPO gene expression (69,71) and iodide transport (72). Hydrocortisone potentiates the TSH-stimulation of iodide transport capacity (14) but does not modify Tg mRNA accumulation (the opposite is found in calf thyroid primary cultures (73)).…”

A tandemly repeated thyroglobulin core promoter has potential to enhance efficacy for tissue-specific gene therapy for thyroid carcinomas

“…18 The presence of tissue specificity is thought to be based on the cell -specific function of the promoter of TG. 19,20 The promoter region of TG has binding sites for thyroid transcriptional factor-1 ( TTF -1), TTF -2, and Pax-8. These trans -acting factors positively regulate the expression of TG at the transcriptional level.…”