Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones suppress transcription of the gene for the beta-subunit of thyrotropin (TSH beta). Since the TSH beta gene in both the mouse and the rat contains two start sites of transcription in exon 1, we have investigated whether expression of the gene from each start site is differentially regulated by thyroid hormones in each species. RNase protection analysis was used to assay the levels of mRNA specifically transcribed from the upstream (TSS 1) and downstream (TSS 2) transcription start sites in the mouse and rat pituitary. In euthyroid and hypothyroid pituitaries there was an approximately 5-fold and 2-fold greater abundance of mRNA derived from TSS 2 than TSS 1, respectively. Hypothyroidism induced an 18- and a 9-fold increase in TSH beta gene expression from TSS 1 and TSS 2, respectively. Treatment of hypothyroid animals for 1 day with triiodothyronine (T3) reduced expression from both start sites by about 50%; after 4 days of T3 treatment, TSH beta mRNAs derived from both start sites were below detectable levels. These results were confirmed in the rat by primer extension analysis. Expression from TSS 1 in the mouse was also shown to be dependent on thyroid status using the polymerase chain reaction (PCR) technique. In contrast to previous results from primer extension studies, PCR analysis demonstrated that alternative splicing of the TSH beta RNA primary transcript can occur when transcription is initiated at the upstream start site. We conclude that, in both the mouse and the rat pituitary, expression of the TSH beta gene from both transcription start sites is regulated by thyroid hormones.
Mol Cell Endocrinol 1990 Jul 09
PMID:Thyroid hormone regulates expression of the thyrotropin beta-subunit gene from both transcription start sites in the mouse and rat. 221 30

Recombinant interleukin-2 (rIL-2; EuroCetus, Amsterdam, Netherlands) was studied in an outpatient phase II trial in 14 patients with progressive metastatic renal carcinoma, malignant melanoma, and colorectal cancer. Escalating doses of rIL-2 were administered as subcutaneous bolus every 12 hours, starting at 0.3 million U/m2/d. A 100% dose increase occurred at weekly intervals, up to a maximum of 2.4 million U/m2/d. Responding patients or patients with stable disease after 4 weeks of rIL-2 (n = 9) were continued on maintenance therapy at 1.8 million U/m2 of rIL-2 administered once weekly. After 12 weeks of therapy, one renal cell cancer patient had a partial regression in lung metastases. Bolus injection of rIL-2 (1.2 million U/m2) resulted in peak serum levels of 25 to 30 U/ml. Toxicity of this regimen was moderate, with local inflammation at the injection sites, grade I-II (World Health Organization) malaise, nausea and/or vomiting, and fevers in 70% to 100% of patients treated. Thyroid dysfunction was observed in 10 patients receiving subcutaneous rIL-2; four of these patients had laboratory evidence of hyperthyroidism, and one had hypothyroidism. rIL-2-induced toxicity reversed spontaneously after cessation of treatment. In all patients receiving rIL-2, a dose-dependent increase in peripheral blood lymphocyte and eosinophil counts was noted, with a mean of 2.6 and 3.8 x 1,000/microliters after 4 weeks of therapy; mean lymphocyte and eosinophil counts were measured at 2.0 and 2.4 x 1,000/microliters in patients who received prior high-dose chemotherapy, compared with 3.2 and 5.1 x 1,000/microliters in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biother 1990 Mar
PMID:Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study. 233 34

Thyroid hormonogenesis in thyroglobulin results in the conversion of an "acceptor" iodotyrosine to a hormone residue and a "donor" iodotyrosine to a dehydroalanine residue. Altogether five acceptor sites have been located as hormone residues in thyroglobulin of different animal species. To search for donor sites, we treated bovine thyroglobulin with 4-aminothiophenol to specifically modify dehydroalanine residues to S-(4-aminophenyl)cysteine (APC) residues, according to the principle of dehydroalanine determination developed by us (Kondo, T., Kondo, Y., and Ui, N. (1988) Mol. Cell. Endocr. 57, 101-106). After digesting thyroglobulin with lysyl endopeptidase, APC-containing peptides were separated from other peptides by trapping them on immobilized naphthylethylenediamine and from each other by size-exclusion and reverse-phase high performance liquid chromatography (HPLC). The HPLC patterns showed about 10 APC-containing peptides. Among them, four different peptides were purified by repeated reverse-phase HPLC. The results of partial sequencing of the four peptides by manual Edman degradation disclosed that Tyr5, Tyr926, Tyr1375, and Tyr986 or Tyr1008 are available for hormonogenesis as donor sites. These results strongly suggest that only specific tyrosine residues behave as donors.
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PMID:Location of dehydroalanine residues in the amino acid sequence of bovine thyroglobulin. Identification of "donor" tyrosine sites for hormonogenesis in thyroglobulin. 234 66

The authors show the direct in vitro action of thyroid hormones on RNA-polymerase activity in rat liver mitochondria. 3,5,3' L-triiodothyronine (L-T3) and 3,5,3',5' L-tetraiodothyronine (L-T4) stimulate mitochondrial RNA synthesis without either increasing the permeability of preswollen mitochondria or stimulating the synthesis of the triphosphate ribonucleotides (NTP's). Thyroid hormones do not directly depress mitochondrial RNA hydrolysis. Studies carried out with structural analogues of thyroid hormones indicate the structural specifications of the regulating system of the mitochondrial RNA-polymerase. L-T3 and L-T4 are also effective 'in vitro' on mitochondria obtained from animals undergoing different hormonal and dietary treatments, with the exceptions of those fed with a hypoprotein diet. Thus, the authors suggest the possible intervention of a specific mitochondrial receptor for L-T3 and L-T4.
Mol Biol Rep 1986
PMID:Direct in vitro action of thyroid hormones on mitochondrial RNA-polymerase. 243 72

Our previous work demonstrated that in vivo estradiol (E2) administration to ovariectomized rats suppressed the transcription of the LH subunit genes within 4 h. To determine whether these effects were mediated directly at the level of the gonadotrope, the transcription rates of the LH beta, FSH beta, and alpha-subunits were measured in short term cultures of pituitary fragments from female rats in various physiological states. In each in vitro experiment, fragments from matched sets of hemipituitaries were used for control and treatment (10(-8)ME2) groups. In pituitaries from ovariectomized animals, treated in vitro with or without E2, there was no significant effect of 2 h or 6 h of E2 on FSH beta or alpha-subunit gene transcription, but a consistent 2- to 3-fold stimulation of LH beta mRNA synthesis. In pituitaries from intact randomly cycling rats, E2 in culture had no effect on the transcription rate of alpha-subunit, FSH beta, or TSH beta genes, but stimulated LH beta and PRL transcription 2-fold. Thyroid hormone treatment specifically suppressed alpha-subunit (38% of control) and TSH beta (17% of control) mRNA synthesis, indicating that the culture system is responding in an appropriate physiological manner and that decreases in transcription can be easily and accurately measured with this system. Basal and E2-treated transcription rates for each gonadotropin subunit gene were measured as a function of stage of the estrous cycle. Basal transcription of the alpha-subunit gene did not vary significantly throughout the cycle and did not respond to E2 treatment in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Mar
PMID:Divergent effects of estradiol on gonadotropin gene transcription in pituitary fragments. 250 67

Thyroid hormones suppress the synthesis of TSH in part by decreasing the rate of alpha and TSH beta gene transcription. Cis-acting DNA sequences present in the rat TSH beta subunit gene that are induced in transcriptional regulation by thyroid hormone have been identified by deletion-mutation and transient expression studies. Plasmid expression vectors were constructed including 2900, 900, 204, 77, 17 base pairs (bp) of 5'-flanking sequence and exon (5'-untranslated sequence, transcriptional start sites) fused to the coding region of the bacterial chloramphenicol acetyltransferase (CAT) gene. The transfected chimaeric plasmids demonstrated expression (with TSH beta DNA sequences in the 5'- to -3'-but not 3'- to -5'-orientation) in both a clonal pituitary cell line, GH3, and primary pituitary cell cultures, both of which are responsive to thyroid hormones. T3 (10(-11) M to 10(-7) M) treatment of transfected cells produced a dose-dependent decrease in CAT expression with a maximal 70% decrease at 10(-8) M. While a decrease in the basal level of expression was noted with progressive removal of both 5'-flanking and intronic sequences adjacent to exon 1, the fold-decrease in response to T3 was equivalent even in the 57 bp construct. In contrast, T3 had no effect on CAT expression directed by the promoter of the herpes simplex virus thymidine kinase gene. Thus, the rat TSH beta gene 5'-flanking region can direct heterologous gene expression in GH3 cells and contains sequences which have properties of a putative cis-active T3 responsive regulatory element(s).2+he
Mol Endocrinol 1989 Apr
PMID:Thyroid hormones regulate rat thyrotropin beta gene promoter activity expressed in GH3 cells. 254 80

It has been proposed from in vivo studies that thyroid angiogenesis during thyroid enlargement may be due to paracrine mitogenic factors released by epithelial thyroid cells. To study this paracrine growth regulating communication between thyroid cells and endothelial cells in vitro, culture medium from isolated porcine thyroid follicles was investigated for a growth promoting effect on porcine aortal endothelial cells. Serum-free conditioned medium (CM) from thyroid follicles in suspension culture contains a dose-related mitogenic activity which stimulates endothelial cell growth up to 197%. Stimulation of the thyroid follicles with TSH (1 mU/ml) significantly reduced the mitogenic activity for endothelial cells in CM to 131%. Thyroid hormones had no influence on mitogenic activity in CM. When follicles were treated with iodide (20 microM) during CM production, no proliferation of endothelial cells was observed by this CM. In contrast, CM from epidermal growth factor-treated thyroid follicles significantly enhanced the mitogenic activity for endothelial cells up to 235%. The mitogenic activity was precipitable by saturated ammonium sulfate, showed high affinity to heparin by chromatography on heparin-sepharose, and was abolished after treatment of CM with trypsin. On gel electrophoresis the heparin-binding fraction showed a double band with a mol wt of 15 and 15.5 k. These data show a paracrine mitogenic activity on endothelial cells released by thyroid follicles which is regulated by TSH, epidermal growth factor, and iodide in parallel with the direct effect of these substances on thyroid cell growth. The data suggest that the mitogenic factor is a polypeptide, which belongs to the heparin-binding growth factors.
Mol Endocrinol 1989 May
PMID:Release of an endothelial cell growth factor from cultured porcine thyroid follicles. 266 51

The thyroid hormones have direct effects on vascular smooth muscle and are potent vasorelaxants. In the present study, the effects of d- and l-thyroxine (d-T4 and l-T4), 3,5,3'-triiodo-d-thyronine (d-T3), and 3,5,3'-triiodo-l-thyronine (l-T3) on the isolated mesenteric artery of the rabbit and superprecipitation of actomyosin from bovine aorta were examined. These thyroid hormones dose dependently relaxed vascular strips previously contracted with 50 mM KCl in the presence of phentolamine (1 microM), propranolol (1 microM), and atropine (0.3 microM), and the order of the inhibitory potency was l-T4 greater than d-T4 greater than l-T3 greater than d-T3 for the contraction. Pretreatment with l-T4 (10 and 30 microM) inhibited the contractile response concomitant with the inhibition of the 20,000-Da myosin light chain phosphorylation, without significant suppression of the increase in La3+-resistant 45Ca influx and uptake (5 and 30 min) induced by 50 mM KCl, suggesting that the inhibitory effect of l-T4 may not be primarily related to Ca2+ entry through the voltage-dependent Ca2+ channel. The l-T4 (10 and 30 microM) showed noncompetitive antagonism against the Ca2+-induced contraction in the high K+-depolarized vascular strips. Superprecipitation of actomyosin was inhibited by the addition of l-T4, in a dose-dependent manner, and calmodulin (1 microgram/ml) partly reversed the inhibitory effect of l-T4. Thyroid hormones were found to inhibit Ca2+/calmodulin-dependent smooth muscle myosin light chain kinase, and the Ki value for l-T4 was 2.5 microM. Although the concentrations of l-T4 used in this study are high, relative to circulating physiological levels, thyroid hormones act directly at the blood vessel wall to cause inhibition of the contractile process in vascular smooth muscle in vitro. Modulation of the 20,000-Da myosin light chain phosphorylation via the inhibition of myosin light chain kinase activity may at least in part contribute to the inhibitory effect of l-T4.
Mol Pharmacol 1989 Jun
PMID:Thyroid hormones directly interact with vascular smooth muscle strips. 273 94

To analyze the regulation of PRL gene expression by thyroid hormone (T3), fusion gene constructs containing various lengths of the rat PRL gene 5'-flanking sequence linked to the bacterial chloramphenicol acetyltransferase (CAT) gene were transfected into the GH3 cell line. Thyroid hormone had no effect on basal or cAMP-stimulated CAT expression in constructs containing more than 1.7 kilobasepairs of the 5'-sequence. However, deletion to 1.5 or 0.6 kilobasepairs resulted in an inhibition of both basal and cAMP-stimulated expression by T3. A construct containing the proximal enhancer region (positions -292 to -38 basepairs) linked to the herpes simplex thymidine kinase promoter (TK) and the CAT reporter gene also responded to T3 with inhibition of basal and cAMP-induced CAT expression. The distal enhancer region (positions -1714 to -1495) linked to thymidine kinase promoter CAT responded to T3 with a stimulation of CAT expression, and the response was additive with the stimulatory response to cAMP. Deletion analysis of the distal enhancer region revealed that the sequence between positions -1530 and -1565 was required for the stimulatory response to T3. The stimulatory response to T3 was additive with the response to estradiol, suggesting distinct elements, but deletion to position -1565 abolished the response to estradiol and permitted an inhibitory response to T3. Mutation of the estrogen response element prevents the response to estradiol, but only blunted the response to T3. Mutation of the sequence GGTCA at positions -1555 to -1551 resulted in an inhibitory response to T3, implicating this sequence in the stimulatory response.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Jun
PMID:Thyroid hormone-responsive elements of the prolactin gene: evidence for both positive and negative regulation. 273 56

Cultures of human thyroid follicles embedded in collagen gel were performed to investigate certain functional properties under bovine thyrotropin (TSH) stimulation. Follicles obtained from normal glands responded to increasing concentrations of TSH administered on day 4 in culture and for 3 days by increased amounts of cyclic AMP (cAMP), thyroglobulin (Tg) and triiodothyronine (T3) and by decreased levels of thyroxine (T4). Effect was maximal at 2000 microU/ml TSH (cAMP) or 200 microU/ml (Tg, T3, T4). When methimazole or propylthiouracil (PTU) were added, the T3 levels decreased. Follicle lumens contained a periodic acid-Schiff substance which was identified by immunoreaction as Tg. Thyroid follicles obtained from Graves' disease glands gave modified results with an earlier and intensified T3 response and no increase in Tg. These data show that (1) Tg and T3 are secretory products of functional follicles giving a cAMP-mediated response to TSH. (2) The detected T3 also derives from T4 5'-deiodination inhibited by PTU. (3) Intensified T3 response in Graves' follicles is probably due to enhanced conversion of T4 to T3.
Mol Cell Endocrinol 1988 Apr
PMID:Functional properties of human thyroid follicles cultured within collagen gel. 283 48


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