Disease relevance of TSHB

• Variable TSH levels ranging from not detectable low to elevated were found so that central hypothyroidism due to a mutation in the TSHB gene was suspected [1].
• Congenital central hypothyroidism (CCH) is a rare disease which can be caused by mutations in the gene for the thyrotropin (TSH) beta subunit ( TSHB) [1].
• Chromogranin A was expressed frequently in adenomas in which at least one of the FSH alpha, FSH beta, LH beta and TSH beta subunits was positive [2].
• Genetic basis of congenital hypothyroidism: abnormalities in the TSHbeta gene, the PIT1 gene, and the NIS gene [3].
• The tissues from pituitary adenomas were obtained at the time of transsphenoidal surgery and revealed immunohistochemically the expression of alpha-subunit and TSH beta in all patients [4].

High impact information on TSHB

• Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non-triodothyronine (T3)-suppressible serum TSH and pituitary TSH-beta mRNA [5].
• Mutation of a critical carboxy-terminal cysteine residue (C105V) in the thyrotropin-beta (TSH-beta) subunit gene was found in two related families with central hypothyroidism [6].
• This natural mutation of the TSH-beta subunit confirms the importance of the seat belt in the family of pituitary and placental glycoprotein hormones [6].
• On the other hand, these agents induced human TSH beta gene expression 4-12-fold in GH3 cells [7].
• cAMP regulation of the human thyrotropin-beta (TSH beta) gene cAMP was studied in two heterologous cell lines, a human embryonal kidney cell line (293) and a rat pituitary cell line (GH3) [7].

Chemical compound and disease context of TSHB

• Light-microscopic indirect immunoperoxidase method applied on formalin-fixed paraffin-embedded specimens revealed alpha-subunit and TSH beta immunoreactivity in all adenomas [8].
• Immunocytochemistry demonstrated glycoprotein expression in somatotroph adenomas (LHbeta: 13%, FSHbeta: 26%, TSHbeta: 30%, alphaSU: 46%) more frequently than in lactotroph, corticotroph and null cell adenomas [9].
• Thyroid hormone inhibition of expression was also conferred to the herpes simplex virus thymidine kinase promoter by inserting +3 to +37 bp of the human TSH beta gene downstream from the start of transcription [10].

Biological context of TSHB

• Transient expression studies were done with various 5'-flanking DNA sequences of TSHB coupled to reporter gene chloramphenicol acetyltransferase [11].
• Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), have been assigned to mouse chromosome 3 and human chromosome 1p22 [12].
• Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), are located less than 310 kb apart in both human and mouse genomes [12].
• The present studies were designed to test the hypothesis that phosphorylation is an important modulator of Pit-1 interaction with the TSH beta gene [13].
• In this study, we have characterized the functional properties of the TGGGTCA motif at -1/+6 of the hTSH beta gene that is similar to the consensus phorbol ester response element (TRE) or the consensus cyclic AMP response element (CRE) [14].

Anatomical context of TSHB

• The human thyroid stimulating hormone beta subunit (TSHB) gene, located on chromosome 1, was studied to determine its subregional location by in situ hybridization and Southern blot analysis of human x mouse hybrid cells [15].
• TSH beta mRNA expression was found only in the pituitary tissue out of other tissues tested as testis, muscle, brain and heart [16].
• These findings suggest that TSH deficiency in this disease is not due to absence of thyrotroph in the pituitary gland or deficiency of TSH-alpha, but to abnormalities of the TSH-beta gene [17].
• T3 did not inhibit TSH-beta gene expression in a T3R-deficient cell line [18].
• Double gold particle immunostaining of the adenomatous tissue removed at surgery showed that all of the cells contained secretory granules positive for alpha-subunit, while very few cells were positive for TSH beta and alpha-subunit [19].

Associations of TSHB with chemical compounds

• In addition, the downstream site overlaps with the recently characterized thyroid hormone-inhibitory element of TSHB [11].
• Regulation of human thyrotropin beta subunit gene (TSHB) expression by thyrotropin-releasing hormone (TRH) was examined in a clonal rat pituitary-cell line (GH3) [11].
• The region between the 10th and 12th cysteine (Cys88-Cys105 in human thyroid-stimulating hormone beta-subunit (hTSHbeta)) of the glycoprotein hormone beta-subunits corresponds to the disulfide-linked seat-belt region [20].
• TRH treatment on pituitary cells increased TSH beta mRNA level, while T4 treatment decreased TSH beta mRNA level [16].
• Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases [21].

Physical interactions of TSHB

• Three regions within the 5'-flanking region of the TSH beta gene have A-T-rich sequences which have sequence similarity to binding sites for the pituitary-specific POU domain transcription factor Pit-1/GHF-1 [22].
• This TRbeta variant (TRbeta2spl) lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSHbeta and glycoprotein hormone alpha-subunit genes in cotransfection studies [23].

Co-localisations of TSHB

• In 7 cases, TSH-beta was positive, and in some cases, TSH-beta was colocalized in the same tumour cells which contained alpha-subunit and FSH-beta subunit [24].

Regulatory relationships of TSHB

• We suggest that both protein kinases C and A as well as TRH share a common mediator which recognizes the TGGGTCA element in activating the hTSH beta promoter [14].
• Conversely, introduction of the hTSHbeta seat-belt sequence into hCGbeta generated an hCG chimera that bound to and activated the TSH receptor but not the CG/lutropin (LH) receptor [20].
• On the other hand, double-staining immunohistochemistry showed that several prolactin (PRL) immunoreactive cells coexpressed TSHbeta within single cells even in normal controls [25].
• NPY suppressed TSHbeta mRNA level, but stimulated alpha-subunit mRNA level [26].

Other interactions of TSHB

• Two tumors that contained TSH beta mRNA by RNAse protection assay also contained Pit-1 mRNA [27].
• We have previously characterized recombinant human TSH (rhTSH) secreted by Chinese hamster ovary cells attached to microcarrier beads in a large scale bioreactor after stable transfection of hCG alpha and hTSH beta minigenes [28].
• The results allowed localization of TSHB to the proximal portion of 1p22, which is in the region of localization of the linkage group including amylase (AMY), nerve growth factor beta subunit (NGFB), and NRAS, which are conserved in humans and rodents [15].
• The human thyrotropin beta (hTSH beta) gene is inducible by various agents including thyrotropin-releasing hormone, phorbol esters, or the adenylyl cyclase activator forskolin [14].
• Replacing the entire seat-belt of hTSHbeta with the hCG sequence conferred full hCG receptor binding and activation to the hTSH chimera, whereas TSH receptor binding and activation were abolished [20].

Analytical, diagnostic and therapeutic context of TSHB

• Analysis of this region by pulsed field gel electrophoresis showed that the genes for TSHB and NGFB are located less than 310 kb apart in man and 220 kb in the mouse [12].
• Molecular cloning of cDNA encoding thyroid stimulating hormone beta subunit of bighead carp Aristichthys nobilis and regulation of its gene expression [16].
• Sequence analysis of the TSH beta-subunit gene (TSHB) showed that the mutation responsible for the hypothyroidism in these families is a nonsense mutation in exon 2 [29].
• Before and 4 months after RIT free triiodothyronine (FT3), free thyroxine (FT4), basal thyroid stimulating hormone (TSHB), stimulated TSH (TSHS), thyroidal technetium uptake (TcTU), and the existence of focal abnormalities in thyroid scintigraphy were evaluated [30].
• Metabolic clearance rates (MCR) of the alpha and beta subunits of human thyrotropin (hTSH-alpha and hTSH-beta) were determined by a constant infusion to equilibrium method [31].

References