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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies carried out in hypophysectomized adult rats have demonstrated that both thyroid hormone and GH can suppress hepatic expression of the steroid 6 beta-hydroxylase P450 2a (IIIA2). The present study further characterizes the influence of thyroid hormone on the expression of P450 2a and two other male-specific hepatic P450s, a steroid 2 alpha/16 alpha-hydroxylase, designated P450 2c (IIC11), and a steroid 15 alpha-hydroxylase, designated P450 RLM2 (IIA2). These studies were carried out in rats rendered hypothyroid by treatment with methimazole, which allows for the nonsurgical depletion of circulating T4, and in hypophysectomized rats. Hypothyroidism led to an increase in hepatic P450 2a (IIIA2) protein and mRNA in both male and female rats that was fully reversed by T4 replacement. In contrast, hypothyroidism decreased by 70-80% the expression of P450 2c (IIC11) activity and mRNA, but did not significantly alter the expression of P450 RLM2 (IIA2). The decrease in P450 2c (IIC11) was not reversed by T4 replacement, suggesting that it is a consequence of the loss of plasma GH pulses that occurs secondary to hypothyroidism. In agreement with these findings, T4 given to hypophysectomized rats partially suppressed the expression of P450 2a (IIIA2) mRNA, but not P450 2c (IIC11) or P450 RLM2 (IIA2) mRNA. A more complete suppression of P450 2a (IIIA2) mRNA as well as P450 2c (IIC11) mRNA was achieved when the hypophysectomized rats were treated with T3 at a supraphysiological, receptor-saturating dose. Although GH administered to intact male rats by continuous infusion fully suppressed all three male-specific P450 proteins and their mRNAs, the same treatment given to hypothyroid rats was only partially suppressive in the case of P450 2a (IIIA2) and P450 RLM2 (IIA2), unless combined with T4. In the case of P450 2c (IIC11), substantial suppression of the residual P450 present in hypothyroid rats was achieved by treatment with GH alone, despite persistent thyroid hormone deficiency. These studies demonstrate that while thyroid hormone is a negative regulator of P450 2a (IIIA2) expression and is required for the full suppression of that P450 and P450 RLM2 (IIA2) by the continuous plasma GH profiles associated with adult female rats, the suppression of P450 2c (IIC11) by continuous plasma GH is largely independent of the presence of thyroid hormone.
Mol Endocrinol 1991 Jan
PMID:Hepatic P450 expression in hypothyroid rats: differential responsiveness of male-specific P450 forms 2a (IIIA2), 2c (IIC11), and RLM2 (IIA2) to thyroid hormone. 201 88

Suppression of two major phenobarbital-inducible cytochrome P-450s, P450IIB1 and P450IIB2, by thyroid hormone was studied and compared with growth hormone (GH)-induced suppression in rats in vivo and hepatocytes in primary culture in vitro. Treatment of adult male rats with 50 micrograms/kg triiodothyronine (T3) reduced the constitutively expressed amounts of P450IIB1 (up to 1 pmol/mg of protein) and P450IIB2 (2-5 pmol/mg of protein) to 42% and 3% of their levels in nontreated controls. Thyroidectomy increased the hepatic contents of P450IIB2 (to levels of 50-80 pmol/mg of protein) and, to a lesser extent, P450IIB1 (1-5 pmol/mg of protein) in male and female rats. Supplement of T3 to thyroidectomized rats reversed the increased contents to levels similar to those observed in normal rats. Hypophysectomy also increased both P450IIB1 and P450IIB2 protein, and their levels in both sexes were similar to that of P450IIB2 in thyroidectomized rats. Treatment of hypophysectomized rats with T3 as well as human GH suppressed hepatic contents of P450IIB1 and P450IIB2. In a hepatocyte culture including 2 mM phenobarbital, T3 and GH suppressed both P450IIB1 and P450IIB2. Other thyroid hormone derivatives, including thyroxine, D-T3, and reversed T3, also showed suppressive effects, in parallel with the potencies for their stimulatory action that have been reported. These results indicate that thyroid hormone may suppress both P450IIB1 and P450IIB2 by a direct effect on the liver, but not by an indirect effect through the modulation of pituitary GH synthesis. The high susceptibility of hepatic P450IIB2 to thyroid hormone-induced suppression also indicates that constitutive and phenobarbital-induced levels of P450IIB2 are suppressively regulated preferentially by thyroid hormone, in contrast to the high susceptibility to GH of P450IIB1 in rat liver. In addition, a difference in the suppressive mechanisms of thyroid hormone and GH was suggested by the difference in susceptibility to cycloheximide.
Mol Pharmacol 1991 Jun
PMID:Difference in the susceptibility of two phenobarbital-inducible forms, P450IIB1 and P450IIB2, to thyroid hormone- and growth hormone-induced suppression in rat liver: phenobarbital-inducible P450IIB2 suppression by thyroid hormone acting directly, but not through the pituitary system. 205 93

We have cloned the human thyroid hormone receptor beta 1 (hThR beta) from the human breast cancer cell line T47D using the PCR technique. A recombinant baculovirus transfer vector pVL1392/hThR beta was constructed and the full length receptor was expressed in the insect cell line Spodoptera frugiperda (Sf9). Approx. 10-15 x 10(6) receptors are expressed/cell which implies a production level of 2.5-4.0 mg hThR beta/l of cell culture. The expressed hThR beta displayed a single class of binding sites for T3 with high affinity. Western blot analysis using a polyclonal antibody indicated that the molecular weight of the baculovirus expressed receptor is approx. 50 kDa. Crude nuclear extract of hThR beta labeled with [125I]T3 sedimented as a 4 S peak on a glycerol gradient. No receptor could be detected in the cytoplasm indicating its proper translocation to the nuclear compartment. An oligonucleotide containing a palindromic thyroid hormone response element is specifically recognized and retarded in a gel-mobility-shift assay in the presence of nuclear extract of Sf9 cells expressing hThR beta. These data suggest that hThR beta expressed in Sf9 cells is functional and displays characteristics virtually indistinguishable from those of the thyroid hormone receptor (ThR) extracted from mammalian cells. Furthermore, the data indicate that the baculovirus expression system is adequate for large-scale production of receptor for detailed structural and functional studies.
J Steroid Biochem Mol Biol 1991 Jun
PMID:High level expression of functional full length human thyroid hormone receptor beta 1 in insect cells using a recombinant baculovirus. 206 82

We have studied the GH-dependent expression of cytochrome P-450IIC12 (P-450(15)beta) mRNA and insulin-like growth factor-I (IGF-I) mRNA in primary adult rat hepatocytes. The GH receptor (GHR), being the common denominator for the GH response, was also studied. The respective mRNA levels were measured with specific solution hybridization assays. By investigating the effects of insulin, IGF-I, T3, and corticosterone, alone or in combinations, in the presence or absence of GH we concluded that GH is indeed the inducer of P-450(15)beta mRNA and IGF-I mRNA. However, insulin and IGF-I exerted a 2-fold potentiation of the GH-induced expression of the P-450(15)beta and IGF-I mRNA species. No significant effect of insulin was observed on GHR mRNA expression, but a translational or posttranslational effect on GHR was seen, in that insulin increased the binding of GH to the cells 4-fold. Furthermore, T3 caused a 9-fold increase in the GH-induced expression of IGF-I mRNA. These observations led us to postulate a possible mechanism of hormonal interplay between GH, thyroid hormone, and IGF-I in vivo, i.e. a thyroid hormone potentiation of the GH-induced IGF-I expression, which, in turn, leads to an increased GHR level and thereby a potentiation of the GH-induced expression of P-450(15)beta and, at least transiently, of IGF-I. A transcriptional mechanism of GH action on P-450(15)beta and IGF-I mRNA induction was indicated by the similar half-lives of respective mRNAs in the presence or absence of GH in cell cultures treated with actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1990 Dec
PMID:Growth hormone (GH) regulation of cytochrome P-450IIC12, insulin-like growth factor-I (IGF-I), and GH receptor messenger RNA expression in primary rat hepatocytes: a hormonal interplay with insulin, IGF-I, and thyroid hormone. 208 91

An abnormal human thyroid hormone beta-receptor (hTR beta-Mf), which has a glycine to arginine substitution in the hormone-binding domain, has been identified in affected members of one family with generalized resistance to thyroid hormone. To better understand the mechanism by which this mutation produces the observed abnormality, expression vectors for the wild-type and mutant thyroid hormone receptors (TRs) were prepared to test hormone-binding activity and trans-activation function. Nuclear extracts of COS-7 cells transfected with wild-type TRs showed specific T3-binding activity, while mutant receptor-transfected COS-7 nuclear extract failed to bind T3. On the other hand, in a avidin-biotin complex DNA-binding assay, in vitro translated hTR beta-Mf showed high binding activity to the thyroid hormone response element, which was indistinguishable from that of wild-type TRs. In a transient expression study, only the wild-type TRs activated a rat GH gene promoter-chloramphenicol acetyltransferase fusion gene in a T3-dependent manner. Additionally, when wild-type TR and hTR beta-Mf were cotransfected, hTR beta-Mf inhibited gene activation regulated by wild-type TRs. From these results we conclude that 1) hTR beta-Mf has no demonstrable T3 binding and appears to have minimal, if any, ability to activate a thyroid hormone-responsive gene in spite of its preserved ability to bind to a TRE in DNA; 2) hTR beta-Mf inhibits the transcriptional activation of a thyroid hormone-responsive gene by the wild-type TRs in a dominant manner; and 3) the dominant negative regulatory function of hTR beta-Mf appears to explain the clinical manifestations of thyroid hormone resistance produced by this mutation when present in the heterozygous state.
Mol Endocrinol 1990 Dec
PMID:Dominant negative transcriptional regulation by a mutant thyroid hormone receptor-beta in a family with generalized resistance to thyroid hormone. 208 93

Activin-A, a homodimeric protein composed of two inhibin beta A-subunits, was first isolated from gonadal fluids based upon its ability to stimulate FSH secretion and biosynthesis, but was also observed to suppress GH secretion. The present report describes the effects of activin on the biosynthesis of GH and the proliferation of pituitary somatotrophs. In pituitary cells cultured in the presence of 0.7 nM activin for 3 days, GH secretion was decreased by 50% compared to the control value. Inhibition of GH biosynthesis, measured by quantitative immunoprecipitation of [35S]methionine-labeled cells, could be observed after 24 h of activin treatment, and maximal (70%) inhibition of GH biosynthesis was observed after 3 days. Activin inhibited basal as well as GH-releasing factor (GRF)-, glucocorticoid-, and thyroid hormone-stimulated GH biosynthesis. Inhibin, which is known to reverse the effect of activin on FSH secretion, did not reverse the effect of activin on GH biosynthesis. Treatment of somatotrophs with activin for 3 days completely inhibited the growth-promoting effect of GRF on somatotrophs. However, no effect of activin on GRF-stimulated expression of the c-fos protooncogene was observed. These data demonstrate that activin, in addition to its stimulatory effect on FSH secretion, is able to inhibit both expression of GH and growth of somatotropic cells.
Mol Endocrinol 1990 Feb
PMID:Inhibition of somatotroph growth and growth hormone biosynthesis by activin in vitro. 210 27

The role of thyroid hormone and GH in the regulation of hypothalamic GH-releasing hormone (GRH) gene expression in the rat was examined after the induction of thyroid hormone deficiency by thyroidectomy. Thyroidectomy resulted in a time-dependent decrease in hypothalamic GRH content, which was significant by 2 weeks postoperatively, and a reduction in pituitary GH content to 1% of the control level by 4 weeks. In contrast, GRH secretion by incubated hypothalami under both basal and K(+)-stimulated conditions was increased after thyroidectomy. Hypothalamic GRH mRNA levels also exhibited a time-dependent increase, which was significant at 1 week and maximal by 2 weeks after thyroidectomy. Administration of antirat GH serum to thyroidectomized rats resulted in a further increase in GRH mRNA levels. T4 treatment of thyroidectomized rats for 5 days, which also partially restored pituitary GH content, lowered the elevated GRH mRNA levels. However, comparable effects on GRH mRNA levels were observed by rat GH treatment alone. These results suggest that the changes in hypothalamic GRH gene expression after thyroidectomy in the rat are due to the GH deficiency caused by thyroidectomy, rather than a direct effect of thyroid hormone on the hypothalamus, since the changes were reversible by GH alone despite persistent thyroid hormone deficiency. In addition, they further support the role of GH as a physiological negative feedback regulator of GRH gene expression.
Mol Endocrinol 1990 Mar
PMID:Effects of thyroid hormone deficiency and replacement on rat hypothalamic growth hormone (GH)-releasing hormone gene expression in vivo are mediated by GH. 211 53

We have used thyroid hormone receptors from two different human cell lines to investigate receptor binding to the promoters of thyroid hormone-responsive genes. Receptors extracted from IM-9 cells or HeLa cells displayed virtually identical affinity and specificity for [125I]triiodothyronine binding. The cells expressed a c-erbA alpha gene in the same relative proportions as the receptor concentrations. Both receptors were bound to DNA-cellulose and could be displaced with increasing concentrations of calf thymus DNA or pBR322 DNA. Relative to pBR322 DNA (designated as 1), binding to the hGH gene promoter was 8.1 +/- 1.1 using the IM-9 cell receptor. With the HeLa cell receptor relative binding was only 1.1 +/- 0.2. Similar relative differences were obtained with the mouse glandular kallikrein gene, mGK-6. In heat stability studies the IM-9 cell receptor was more resistant to heat inactivation than the HeLa receptor. Triiodothyronine receptors with identical hormone binding patterns may require the presence of an unidentified factor(s) which allows correct recognition of regulation sequences within responsive genes.
Mol Cell Endocrinol 1990 Mar 05
PMID:Thyroid hormone receptors from IM-9 cells but not HeLa cells bind to promoters of triiodothyronine-responsive genes. 215 65

To determine the capacity of the chicken c-erbA (cTR-alpha) gene product in regulating expression of known thyroid hormone-responsive genes, both the cTR-alpha and the viral v-erbA genes were expressed in FAO cells, a rat hepatoma cell line defective for functional thyroid hormone receptors. Upon nuclear expression of the cTR-alpha protein the cells become responsive to thyroid hormone, as detected by expression of a number of genes (malic enzyme, phosphoenolpyruvate carboxykinase, and Na+/K(+)-ATPase) reported to be indirectly induced by the hormone in vivo. In addition, our data show that the c-erbA product directly activates the Moloney murine leukemia virus promoter in a ligand-dependent manner. The data show that the chicken c-erbA-alpha protein can modulate the expression of rat genes under either direct or indirect control by thyroid hormone.
Mol Endocrinol 1990 Feb
PMID:The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells. 215 23

The proto-oncogenes erbA alpha and erbA beta together encode three functional thyroid hormone receptors (erbA alpha 1, beta 1, and beta 2), as well as two proteins (erbA alpha 2 and alpha 3) that do not bind T3. The erbA alpha 2 protein has been shown to inhibit the T3 inductive effects of functional receptors, and alpha 2 mRNA is expressed at high levels in adult rat brain. Thus, expression of erbA alpha 2 may explain the observation that adult rat brain is not a T3 responsive organ, despite the presence of T3 receptors. However, expression of the different erbA mRNAs has not been studied within distinct regions of rat brain. To gain further insight into the roles of these molecules, we have used polymerase chain reaction to investigate the expression of all five erbA mRNAs within discrete regions of adult rat brain. The results indicate that all three erbA alpha mRNAs are expressed in all regions studied (brainstem, cerebellum, cortex, hippocampus, pituitary, quadrigeminal plate, striatum, and thalamus). All regions contained less erbA alpha 3 RNA than either alpha 1 or alpha 2. Expression of alpha 2 exceeded that of alpha 1 in all regions except striatum. ErbA beta 1 was expressed in all brain regions, whereas erbA beta 2 was confined to the pituitary.
Mol Cell Endocrinol 1990 Mar 26
PMID:Expression of erbA alpha and beta mRNAs in regions of adult rat brain. 216 Mar 81


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