title: 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 Gq/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 Gq/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.
authors.affiliation: Medical Department III, University Hospital Aachen, D-52074 Aachen, Germany.
authors.forename: Christer M
authors.initials: CM
authors.lastname: Bäck
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stohr
authors.forename: Eva A M
authors.initials: EA
authors.lastname: Schäfer
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boekhoff
authors.forename: Andreas
authors.initials: A
authors.lastname: Breit
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Thomas R H
authors.initials: TR
authors.lastname: Büch
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D011989:Receptors, Thyrotropin; C407523:metallothionein isoform 1; D000255:Adenosine Triphosphate; D002217:Carbachol; D013972:Thyrotropin; D008668:Metallothionein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium
keywords: Calcium; Gq/11; TSH receptor; metallothionein; protein kinase C; signal transduction