TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling

Abstract

Metallothioneins (MTs) are cytoprotective proteins acting as scavengers of toxic metal ions or reactive oxygen species. MTs are upregulated in follicular thyroid carcinoma and are regarded as a marker of thyroid stress in Graves' disease. However, the mechanism of MT regulation in thyrocytes is still elusive. In other cellular systems, cAMP-, calcium-, or protein kinase C (PKC)-dependent signaling cascades have been shown to induce MT expression. Of note, all of these three pathways are activated following the stimulation of the TSH receptor (TSHR). Thus, we hypothesized that TSH represents a key regulator of MT expression in thyrocytes. In fact, TSHR stimulation induced expression of MT isoform 1X (MT1X) in human follicular carcinoma cells. In these cells, Induction of MT1X expression critically relied on intact G q/11 signaling of the TSHR and was blocked by chelation of intracellular calcium and inhibition of PKC. TSHR-independent stimulation of cAMP formation by treating cells with forskolin also led to an upregulation of MT1X, which was completely dependent on PKA. However, inhibition of PKA did not affect the regulation of MT1X by TSH. As in follicular thyroid carcinoma cells, TSH also induced MT1 protein in primary human thyrocytes, which was PKC dependent as well. In summary, these findings indicate that TSH stimulation induces MT1X expression via G q/11 and PKC, whereas cAMP-PKA signaling does not play a predominant role. To date, little has been known regarding cAMP-independent effects of TSHR signaling. Our findings extend the knowledge about the PKC-mediated functions of the TSHR.

Brain and Hepatic Mt mRNA Is Reduced in Response to Mild Energy Restriction and n-3 Polyunsaturated Fatty Acid Deficiency in Juvenile Rats

“…Previous reports demonstrate that Mt3 mRNA is reduced by thyroxine in the developing rat brain [ 18 ]. Moreover, MT mRNA and protein levels are inducible by thyroid-stimulating hormone (TSH), and their induction is considered a thyroid stress marker of autoimmune diseases [ 52 , 53 ]. Studies in mammals report that ER decreases TH (T3 and/or T4) in serum or plasma [ 54 , 55 ].…”

Thyrostimulin-TSHR signaling promotes the proliferation of NIH:OVCAR-3 ovarian cancer cells via trans-regulation of the EGFR pathway

“…Indeed, it has been reported that gonadotropins can activate ERK signaling via both the calcium-dependent and PKCδ-dependent mechanisms and this subsequently leads to the promotion of EOC cell proliferation and migration 25 . Like the activity of gonadotropin receptors in the ovarian cells, several studies have also reported that activation of TSHR can turn on calcium and PKC signaling in thyrocytes 41 42 . Therefore, although TSHR signaling has not yet been well characterized in the ovarian cancer cells, one may speculate that it can also activate the calcium and PKC pathways, which may then contribute to at least part of the thyrostimulin-induced ERK activation.…”

A Gq Biased Small Molecule Active at the TSH Receptor

“…For example, conditional deletion of Gα q/11 in mouse thyroid resulted in hypoplastic thyroid glands and severe hypothyroidism (34). It has also been shown that Gα q/11 -PKC dependent activation in TSHR transfected papillary cancer cells (line FTC236) resulted in the upregulation of a class of redox and metal ion scavengers which are cysteine-rich proteins known as metallothioneins (MTs) (37). Studies have also shown an indirect relationship of Gα q/11 activation to thyroid peroxidase formation (34,38) and a congenital hypothyroidism phenotype (39).…”