Disease relevance of TSHZ1

• Although we had previously demonstrated a 50-fold increase in hTSH secretion rates in primary hypothyroidism, there was only a 2-fold increase in alpha and hTSH-beta secretion rates [1].
• The hTSHbeta.CTPalpha(1+2) variant blocked cAMP formation and thyroid hormone secretion stimulated by hTSH as well as by the antibody, thyroid-stimulating immunoglobulins, responsible for the most common cause of hyperthyroidism, Graves disease [2].
• Its predominant presence in thyroiditis extracts seems important in view of the already described immunological heterogeneity of pituitary hTSH [3].
• Asialo-hCG purified from a patient with choriocarcinoma had very potent TSH-like activity (468 microU hTSH/mg) [4].
• Deglycosylated hCG, a very weak LH/hCG receptor agonist, was the most potent agonist in thyroid follicles (588 microU hTSH/mg protein). hCGs purified from urine of patients with trophoblastic tumors had greater TSH-like activity (37-84 microU hTSH/mg protein) than purified hCG [4].

Psychiatry related information on TSHZ1

• The sensitivity of the autoregulatory system to the suppressive effects of exogenous hTSH decreased with increasing duration of hypothyroidism; a time-response relationship existed [5].

High impact information on TSHZ1

• We describe chimeras of two glycoprotein hormones, human chorionic gonadotropin (hCG) and human follitropin (hFSH), that exhibit activity unique to a third family member, human thyrotropin (hTSH) [6].
• The specificity of TSH binding to these peptides was confirmed by their inability to bind human luteinizing hormone, human follicle-stimulating hormone, and the alpha chain of hTSH [7].
• The single chain variants were expressed in CHO cells and were secreted into the medium. hTSH variants lacking the oligosaccharide chains were less potent than hTSHbeta.CTPalpha wild-type with respect to cAMP formation and thyroid hormone secretion in cultured human thyroid follicles [2].
• Alanine cassette mutagenesis of hTSH showed that the Cys95-Cys105 segment of the seat-belt was more important for TSH receptor binding and signal transduction than the Cys88-Cys95 determinant loop region [8].
• To characterize the role of this region for hTSH, we constructed hTSH chimeras in which the entire seat-belt region Cys88-Cys105 or individual intercysteine segments Cys88-Cys95 and Cys95-Cys105 were replaced with the corresponding sequences of hCG and hFSH or alanine cassettes [8].

Biological context of TSHZ1

• None of the nine monoclonal antibodies, termed beta-hCG-CTPa1----a9, reacted with hLH, hFSH, or hTSH, although these pituitary hormones display extensive amino acid sequence homology with hCG [9].
• Similarly, residues alpha Arg42-Ser43-Lys44 were more important for hTSH-mediated induction of cell growth than cAMP production [10].
• A 17 kilobase pair fragment of DNA containing the human TSH (hTSH) beta-subunit gene was isolated from a human leukocyte genomic library [11].
• In the present study, we compared the role of specific amino acids within this region for glycoprotein hormone heterodimer formation, using a transient transfection system to coexpress different mutant alpha-subunit constructs with the beta-subunit of either hTSH, hCG, or hFSH [10].
• The hTSH synthesized in 293 cells was glycosylated as indicated by complete binding to concanavalin A-Sepharose but was larger in apparent molecular weight than a standard hTSH preparation on gel chromatography suggesting an altered glycosylation pattern [11].

Anatomical context of TSHZ1

• A similar fetomaternal difference existed also for plasma hGH, in contrast to plasma hLH/hCG, which concentration was higher in maternal than in fetal blood LRH did not cause any change of circulating hFSH, hLH/hCG, and hTSH levels in the fetus 10 min after its administration [12].
• The concentrations of hFSH, hLH/hCG, hGH, and hTSH1 were measured in maternal and fetal blood during the second trimester of pregnancy before and after the administration of 10 mug LRH to 9 fetuses [12].
• To devise an in vitro FSH bioassay suitable for exploring this mechanism, we expressed hFSH-R complementary DNA in COS-7 cells and stimulated them with recombinant hTSH (rec-hTSH) [13].
• Wild-type hTSH and the single chains were expressed in Chinese hamster ovary (CHO) cells, and they were efficiently secreted [14].
• Inhibition of [125I]hTSH binding to solubilized porcine membranes (TSH-receptor auto-antikörper assay) or Chinese hamster ovary cell membranes previously transfected with hTSH-R gene showed that mAb 34A recognizes the hTSH-binding site of both receptors [15].

Associations of TSHZ1 with chemical compounds

• Maximum inhibition by the mAb of hTSH stimulation of adenylate cyclase ranged from 3-92% [16].
• However, it was immunologically and biologically indistinguishable from two pituitary hTSH standards in an immunoradiometric and in vitro iodide trapping assay, respectively [11].
• Amplification of the transfected sequences by methotrexate selection, followed by cell culture in a hollow fiber perfusion system, yielded rec hTSH production as high as 100,000 microU/ mL [17].
• Serum T4 cortisol, hGH, hPRL, and hTSH levels were normal [18].
• The addition of bovine TSH (bTSH) or human TSH (hTSH) resulted in dose-dependent reduction in polyethylene glycol-precipitable radioactivity, though hTSH was much less effective [19].

Analytical, diagnostic and therapeutic context of TSHZ1

• Thus, exchanging the seat-belt region between hTSH and hCG switches hormonal specificity in a mutually exclusive fashion [8].
• A multianalyte immunoassay for simultaneous detection of three analytes (hTSH, hCG and beta-Gal) has been demonstrated using DNA-labeled antibodies and polymerase chain reaction (PCR) for amplification of assay response [20].
• In summary, using site-directed mutagenesis, we identified a domain, residues 33-44 of the common alpha-subunit, important in heterodimer expression, receptor binding, and activation of hTSH [10].
• Pituitary extracts from five patients with atrophic asymptomatic thyroiditis and from five subjects without any endocrine disease, matched for sex and age, were passed through gel filtration columns and the collected fractions were analyzed in three different radioimmunoassays (hTSH-anti-hTSH; hTSHbeta-anti-pTSH; hLHAlpha-anti-LHalpha) [3].
• Rec-hTSH elicited a dose-dependent cAMP response in the in vitro hFSH-R bioassay; however, the concentration of rec-hTSH required for half-maximal stimulation was several logs greater than that of hFSH [13].

References