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During the menstrual cycle, the ovarian hormones oestradiol and progesterone control the ordered growth and differentiation of uterine cells. This remodelling process is critical for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. Failure of uterine tIssues to respond appropriately to ovarian hormone signalling results in defective placentation, associated with a spectrum of pregnancy disorders such as recurrent miscarriages and preeclampsia. These obstetrical disorders are a major cause of maternal and perinatal morbidity and mortality. Progesterone exerts its action on target cells, at least in part, through binding to the progesterone receptor (PR), a member of the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualization, in the secretory phase of the menstrual cycle is not well understood. Emerging evidence indicates that locally expressed factors and activation of the cAMP second messenger pathway integrate hormonal inputs and confer cellular specificity to progesterone action through the induction of diverse transcription factors capable of modulating PR function.
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Abstract
In order to study whether peripheral action of thyroid hormones is altered in insulin deficiency and to elucidate the biological consequences of alteration of the cytosolic 3,5,3′-tri-iodo-l-thyronine (T3) binding protein (CTBP), we measured malic enzyme, T3-responsive nuclear n protein, CTBP and nuclear thyroid hormone receptor in the liver and kidney of streptozotocin (STZ)-induced diabetic rats that were treated with or without insulin and/or a receptor-saturating dose of T3. The following results were obtained. 1. Induction of malic enzyme by T3 was apparently diminished in diabetic rats. However, supplementary injection of insulin enabled previously given T3 to take effect in diabetic rats. 2. T3-responsiveness of other hepatic proteins (n protein and CTBP) was not altered by insulin in diabetic rats. 3. The level of n protein was increased by insulin in diabetic rats in vivo and in perfused rat liver, indicating that the hepatic n protein is a novel insulin-responsive protein. T3 and insulin increased the level of n protein non-synergistically in diabetic rat liver. 4. Hepatic nuclear receptor levels were not altered in diabetic rats. 5. Hepatic CTBP levels were decreased in diabetic rats. This was not due to the toxic effect of STZ. Low CTBP level was only partially increased by insulin after 30 days of diabetic period. Renal CTBP levels were not altered in diabetic rats with or without insulin treatment. These results indicate that reduction of CTBP did not influence the hepatic response to a receptor-saturating dose of T3, although CTBP may regulate the nuclear T3 transport, and that fundamental action of a receptor-saturating dose of T3 was not attenuated in diabetic rat liver.
Journal of Endocrinology (1994) 143, 55–63
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The aim of this study was to evaluate developmental changes in thyroid hormone and other key endocrine hormones/molecular markers produced by testicular cells, in relation to breed differences in proliferation and maturation of Sertoli cells and general testicular morphological development in Meishan (MS) and White Composite (WC) boars. Blood samples and testes were collected on days 60, 75, 90 and 105 post coitum (dpc) and days 1, 7, 14 and 25 post partum (dpp). Testes were immunostained for thyroid hormone receptor-beta1 (THRbeta1), GATA4, Mullerian-inhibiting substance (MIS), 17-alpha-hydroxylase (P450(c17)) and inhibin subunits (alpha, betaA, betaB). In addition, protein levels were determined by densitometry. Plasma concentrations of free triiodothyronine (T(3)) were greater in MS (hyperthyroid) compared with WC (hypothyroid) boars (P<0.01) during fetal life, but the reverse was evident postnatally. Elevated levels of free T(3) during fetal life were associated with increased levels of THRbeta1, suggesting increased thyroid responsiveness of the testis during this time, contrasting with observations during early postnatal life. Localization patterns of THRbeta1, MIS, GATA4 and the inhibin subunits were consistent with previous studies. MIS protein levels declined more rapidly (P<0.001) in MS compared with WC Sertoli cells postnatally, consistent with earlier maturation of Sertoli cells as indicated by our previous study. In this study, transient neonatal hyperthyroidism in MS boars during late gestation was associated with a decline in proliferation and early maturation of Sertoli cells, followed by early onset of puberty in this breed. These observations indicate a possible role for thyroid hormone in the modification of Sertoli cell development, thereby influencing growth and differentiation of the testis in pigs.
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We have previously described a panel of human small cell lung carcinoma (SCLC) cell lines that have profound glucocorticoid resistance, resulting from various molecular defects in glucocorticoid signalling. However, in one SCLC cell line, CORL103, the cause of the resistance is unknown. These cells are refractory to dexamethasone stimulation of MMTV even when exogenous wild-type glucocorticoid receptor (GR) is co-transfected. This is in contrast to cell lines DMS79 and CORL24 where resistance is overcome by transfection of the wild-type receptor. Sequencing of the GR from CORL103 cells revealed two point mutations, but neither of these induced dominant negative activity. Steroid hormone resistance extended to mineralocorticoid and progesterone receptor (MR, PR) activation of MMTV-luc, whereas oestrogen and thyroid hormone receptor transactivation were normal. A simpler reporter, TAT3-luc, containing three copies of the tyrosine aminotransferase glucocorticoid response element (GRE), was responsive when transfected into CORL103 cells with GR, MR and PR expression vectors and activated with their respective ligands. Similarly, pHH-luc and pAH-luc (truncated MMTV variants containing the GRE region, both derived from a different strain of MMTV), were effectively transactivated with dexamethasone. This suggests that the minor changes in the flanking sequence of the MMTV promoter are critically important in determining steroid responsiveness in CORL103 cells. We propose that minor differences in MMTV may determine recruitment of co-factors, which destabilise GR binding to the MMTV GREs. These findings represent a new, selective, model of glucocorticoid resistance that may explain specific cell and target gene differences in glucocorticoid sensitivity.
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Postnatal Sertoli cell maturation is characterized by a pronounced rise in androgen receptor (AR) expression, which increases several fold between birth and adulthood. Since both 3,3',5-triiodothyronine (T3) and FSH regulate Sertoli cell proliferation and differentiation, we have determined the effects of T3 and FSH on AR mRNA expression in cultured Sertoli cells from 5-day-old rats. These cultures contain 5-9% peritubular cells, which also express AR mRNA. To insure that the observed T3 responses did not result from peritubular cells, we examined T3 effects on AR mRNA expression in cultured 20-day-old Sertoli cells (which contain minimal peritubular contamination) and peritubular cells, and measured thyroid hormone receptor (TR) mRNA expression in both of these cell types. Sertoli cells from 5- and 20-day-old rat testes were grown in serum-free medium alone (controls) or with ovine FSH (100 ng/ml) and/or T3 (100 nM) for 4 days. Peritubular cells purified from 20-day-old rat testes were grown in serum-containing medium for 8 days. These cells were split 1:4, and grown an additional 8 days, the last 4 days in serum-free medium with or without T3. TR and AR mRNA levels in all cultures were determined by Northern blotting. AR mRNA levels in 5- and 20-day-old cultured Sertoli cells were significantly (P < 0.05) increased by both T3 and FSH alone. Furthermore, AR mRNA levels in Sertoli cells treated with T3 and FSH were greater than with either alone. TR mRNA expression was detected in cultured peritubular cells, but TR mRNA levels in these cells were only approximately 30% of that seen in 20-day-old cultured Sertoli cells. In contrast to Sertoli cells, T3 did not affect peritubular AR mRNA expression. These results indicate that T3 is an important regulator of the postnatal Sertoli cell AR mRNA increase. The additive effects of maximally stimulatory doses of FSH and T3 suggest these hormones work through different mechanisms to increase AR mRNA. TR mRNA expression in peritubular cells indicates these cells may be direct T3 targets, though the function of T3 in these cells is unknown.
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N-TERA-2 cl/D1 (NT2) cells, a human embryonal cell line with characteristics of central nervous system precursor cells, were utilised to study thyroid hormone action during early neuronal growth and differentiation. Undifferentiated NT2 cells expressed mRNAs encoding thyroid hormone receptors (TRs) alpha1, alpha2 and beta1, iodothyronine deiodinases types 2 (D2) and 3 (D3) (which act as the pre-receptor regulators), and the thyroid hormone-responsive genes myelin basic protein (MBP) and neuroendocrine specific protein A (NSP-A). When terminally differentiated into post-mitotic neurons (hNT), TRalpha1 and TRbeta1 mRNA expression was decreased by 74% (P=0.05) and 95% (P<0.0001) respectively, while NSP-A mRNA increased 7-fold (P<0.05). However, mRNAs encoding TRalpha2, D2, D3 and MBP did not alter significantly upon neuronal differentiation and neither did activities of D2 and D3. With increasing 3,5,3'-triiodothyronine (T(3)) concentrations, TRbeta1 mRNA expression in cultured NT2 cells increased 2-fold at 10 nM T(3) and 1.3-fold at 100 nM T(3) (P<0.05) compared with that in T(3)-free media but no change was seen with T(3) treatment of hNT cells. D3 mRNA expression in NT2 cells also increased 3-fold at 10 nM T(3) (P=0.01) and 2.4-fold at 100 nM T(3) (P<0.05) compared with control, but there was no change in D3 enzyme activity. In contrast there was a 20% reduction in D3 mRNA expression in hNT cells at 10 nM T(3) (P<0.05) compared with control, with accompanying reductions in D3 activity with increasing T(3) concentrations (P<0.05). There was no significant change in the expression of the TRalpha isoforms, D2, MBP and NSP-A with increasing T(3) concentrations in either NT2 or hNT cells. Undifferentiated NT2 and differentiated hNT cells show differing patterns of T(3)-responsiveness, suggesting that there are different regulatory factors operating within these cell types.
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( Fig. 2 C). Figure 2 Effect of fish oil on hepatic thyroid hormone receptor expression of euthyroid (EU) and hypothyroid (HYPO) animals. (A) Hepatic TRβ1 expression evaluated by western blotting (representative autoradiography and graphic representation
Local control of thyroid hormone action: role of type 2 deiodinase
Deiodinases: the balance of thyroid hormone
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Introduction Thyroid hormones are important homeostatic regulators that act via nuclear thyroid hormone receptors (TRs) in virtually all tissues during development and throughout postnatal life. 3,5,3′,5′- l -tetraiodothyronine (thyroxine, T 4 ) is
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brain. Figure 3 Model of thyroid hormone transport and metabolism in the rodent brain. O1, OATP1C1; M8, MCT8; TR, thyroid hormone receptor. MCT8 and OATP1C1 are present in the endothelial cells of microvessels, where they facilitate the transport
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, USA
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which T3 prevents activated FOXO1 activity is unclear. Thyroid hormone receptors and actions Research into the signaling biology of thyroid hormone is a dynamic area, at present, because of newly discovered signaling pathways through
