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PubMed1996

Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states.

Transactivation-defective retinoid X and thyroid hormone receptors have been used to examine mechanisms of hormonal activation. Activation and repression of transcription by retinoid X and thyroid hormone receptors are shown to be mediated by physically distinct and functionally independent regions of the hormone binding domain. Nevertheless, the ability of receptors to respond to hormone requires communication between both functional domains. Deletion of the hormone-dependent transactivation function of the retinoid X receptor, the common subunit of heterodimeric nuclear receptors, significantly impairs hormone-dependent transcription by retinoic acid, thyroid hormone, and vitamin D receptors. The results indicate that receptors do not exist in static off and on conformations but that hormone alters an equilibrium between inactive and active states.

Animals↗
PubMed1992

A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5.

The distal portion of the long arm of human chromosome 5 contains an impressive number of genes encoding growth factors, growth factor receptors, and hormone/neurotransmitter receptors. The order of and relative distance between 18 of these genes was determined by radiation hybrid mapping. There is only a single gap in a contiguous radiation map from 5q22-5q35. For this set of radiation hybrids, one map unit (centiray) corresponds to 20-50 kb of DNA. Close physical proximity for several pairs of loci was predicted by the map. Two sets of these were found to be contained in single YAC clones. The physical map produced by radiation hybrid mapping should prove useful in efforts to identify four disease genes that have been assigned to distal 5q by linkage studies.

Base Sequence↗
PubMed2004

Novel mode of deoxyribonucleic acid recognition by thyroid hormone receptors: thyroid hormone receptor beta-isoforms can bind as trimers to natural response elements comprised of reiterated half-sites.

Thyroid hormone receptors (TRs) regulate gene expression by binding to specific DNA sequences, denoted thyroid hormone response elements (TREs). The accepted paradigm for TRs proposes that they bind as homo- or heterodimers to TREs comprised of two AGGTCA half-site sequences. In the prototypic TRE, these half-sites are arranged as direct repeats separated by a four-base spacer. This dimeric model of TR binding, derived from analysis of artificial DNA sequences, fails to explain why many natural TREs contain more than two half-sites. Therefore, we investigated the ability of different TR isoforms to bind to TREs possessing three or more half-sites. We report that the TRbeta isoforms (TRbeta0, TRbeta1, TRbeta2), but not TRalpha1, can bind to reiterated DNA elements, such as the rat GH-TRE, as complexes trimeric or greater in size. The TRbeta0 isoform, in particular, formed homo- and heterotrimers (with the retinoid X receptor) with high efficiency and cooperativity, and TRbeta0 preferentially used reporters containing these reiterated elements to drive gene expression in vivo. Our data demonstrate that TRbeta isoforms can form multimeric receptor complexes on appropriately reiterated DNA response elements, providing a functional distinction between the TR isoforms and an explanation for TREs possessing three or more half-sites.

Animals↗
PubMed1996

Messenger ribonucleic acid expression for growth hormone receptor, luteinizing hormone receptor, and steroidogenic enzymes during the estrous cycle and pregnancy in porcine and bovine corpora lutea.

Growth hormone (GH) and luteinizing hormone (LH) are pituitary hormones involved in steroidogenesis in the corpus luteum (CL). The objectives of Experiment I were to determine mRNA expression for GH receptor (GHR) and LH receptor (LHR) in porcine luteal tissues during the estrous cycle and pregnancy and to relate changes in these receptor mRNA with changes in steroidogenic enzyme mRNA for cytochrome P450 side-chain cleavage enzyme (P450sec) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). Ovaries were collected from gilts during the estrous cycle (day 10 [n = 3] and Day 19 [n = 3, regressed CL) and pregnancy (Day 25 [n = 3] and Day 44 [n = 3]). Tissues were frozen in liquid nitrogen and sectioned. Messenger RNA was detected by in situ hybridization, and relative mRNA amounts were determined by image analysis. The mRNA for GHR, LHR, P450sec, and 3 beta-HSD were detected in the CL on Day 10 of the estrous cycle. None of these mRNA were specific to cither large luteal cells (LLC) or small luteal cells (SLC). On Day 19 of the estrous cycle (regressed CL), mRNA for GHR, P450sec, and 3 beta-HSD were decreased (P < 0.01) whereas LHR mRNA disappeared (P < 0.01). During pregnancy, mRNA expression increased 2.1-, 1.4-, 1.4-, and 1.2-fold for GHR, LHR, P450sec, and 3 beta-HSD, respectively (P < 0.05). The luteal location of GHR mRNA in the pig did not agree with that found in our previous studies of GHR mRNA or protein in cattle. Therefore, the objective of Experiment 2 was to measure GHR mRNA by the use of in situ hybridization in bovine CL during the estrous cycle (Day 14; n = 2) and pregnancy (Day 25; n = 2). In situ hybridization demonstrated specific expression of GHR mRNA in the LLC of cattle. Furthermore, GHR mRNA increased 1.8-fold in CL on Day 25 of pregnancy compared with GHR mRNA on Day 14 of the estrous cycle (P < 0.01). In adjacent sections, the LHR mRNA was most highly expressed in clusters of SLC with 1.6-fold more mRNA on Day 25 of pregnancy compared with Day 14 of the estrous cycle (P < 0.01). These results suggest that: 1) mRNA for LHR, GHR, P450sec, and 3 beta-HSD are differentially regulated during the estrous cycle and pregnancy and 2) the cellular location of GHR differs for pigs and cattle, with highly specific expression of GHR in bovine LLC but not porcine LLC. This may suggest different functions for GH in the CL of these species.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

[The significance of hormone receptors in hormone therapy of gastric cancers].

The influence of sex hormones on carcinogenesis of the stomach was investigated clinically and experimentally. Thereafter, hormone therapy for Borrmann type 4 gastric cancers was started and achieved good results according to some reports. The presence of hormone receptors (ER and PGR), which are detected in 10-20% of gastric cancers, was one of the bases of that therapy. However, the role of hormone receptors in hormone therapy is not clear because the stomach is not the target organ of sex hormones. The mechanisms of hormone effects on cancer therapy have been described as follows: (a) Hormone receptors play an important role in stimulating the proliferation of cells via hormone-receptor complexes. (b) Hormones play a direct role in stimulating the proliferation of cells without any involvement of receptors. We found evidence that sex hormones might suppress the growth of some stomach cancers. On that basis, we started a trial of a hormone therapy using tamoxifen in females and estriol in males after radical surgery for Borrmann type 4 gastric cancer. We hope to obtain good results in this new trial.

Adult↗
PubMed1999

Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma.

OBJECTIVES: Tamoxifen is a nonsteroidal triphenylethylene derivate with a predominant antiestrogen activity, used in the endocrine treatment of breast and endometrial cancer. It is not known which endometrial carcinomas will respond favorably to tamoxifen and which ones will not. The aim of this study was to find out whether tamoxifen has an effect on hormone steroid receptors, hormone concentration, DNA content, and proliferative activity in endometrial cancer and to correlate the tamoxifen-induced changes with pathologic parameters such as clinical stage, tumor differentiation, depth of invasion, and histologic type. METHODS: Thirty postmenopausal women with endometrial carcinoma were treated with 30 mg of tamoxifen daily for 7-10 days after curettage. Steroid hormone receptors (estrogen and progesterone receptors), levels of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone, testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and DNA ploidy and proliferative activity were determined before and after therapy. The patients were also divided into favorable and unfavorable prognosis groups according to classical histological parameters. The patients in the favorable group consisted of patients with stage I disease, well and moderately differentiated tumors, favorable histologic type, and a depth of myometrial invasion of less than (1/3). The patients with only one of the unfavorable parameters (clinical stage II or III, poorly differentiated tumors, unfavorable histologic types, and deeper invasion of myometrium) were included in the unfavorable prognosis group. RESULTS: After the treatment, there was a net increase in the progesterone receptors and sex hormone binding globulin and a significant decrease in the estrogen receptors. The increase in progesterone receptors and decrease in estrogen receptors occurred in the patient group with favorable prognosis regarding histologic type, degree of differentiation, and clinical stage, but also in the unfavorable prognosis group regarding the depth of myometrial invasion. Statistically significant decrease in the follicle-stimulating hormone concentration was observed in the groups with favorable prognosis regarding histologic type, depth of myometrial invasion, and grade of differentiation. Concentration of sex hormone binding globulin was significantly increased in groups with favorable prognosis if histologic type and grade of differentiation were taken into account. On the other hand, there was a significant decrease in the concentration of luteinizing hormone in the group with unfavorable histologic type and also a decrease in progesterone concentration in patients with unfavorable prognosis regarding the grade of differentiation. There was no statistical significance either in the concentrations of other hormones measured or in the DNA analysis by flow cytometry. CONCLUSIONS: Our results revealed that tamoxifen can increase progesterone receptors and decrease estrogen receptors in endometrial cancer. The effect was most pronounced in tumors with favorable clinicopathologic parameters. We conclude that tamoxifen therapy can induce progesterone receptor synthesis even in tumors with low initial progesterone receptor levels, making such tumors potentially responsive to additional hormonal therapy with progesterone.

Adenocarcinoma↗
PubMed1988

Conformational transition of thyroid hormone receptor upon hormone binding: demonstration by aqueous two-phase partitioning.

An aqueous two-phase partitioning study of partially purified nuclear thyroid hormone receptor from rat liver was performed. Stability of 3,5,3'-tri-iodo-L-thyronine (T3)-receptor complex and T3-binding activity in the presence of dextran or polyethylene glycol were assessed in order to determine the amount of occupied or unoccupied receptors in each phase. Partition coefficients were calculated as the ratio of receptor concentration in the upper polyethylene glycol-rich phase H2O and that in the lower dextran-rich phase H2O. The partition coefficient was a sensitive function of the salt at pH above 6.1 and below 5.1. The salt had no effect on the partition coefficient at pH around 5.6. These results suggest that the isoelectric point of the thyroid hormone receptor is about 5.6, confirming previous determinations using isoelectric focusing. The partition coefficient of the receptor decreased upon T3 binding, regardless of the salt composition. In contrast, the partition coefficient of thyroxine-binding globulin increased upon T3 binding. Free T3 preferentially partitioned into the upper polyethylene glycol-rich phase and gave a partition coefficient higher than 1.0. These results strongly suggest that the decrease in the partition coefficient of the receptor upon hormone binding reflects conformational changes or changes in electrostatic properties of the receptor upon hormone binding. Such an alteration may be involved in biological activation of the receptor upon hormone binding.

Animals↗
PubMed1995

Differential roles of exoloop 1 of the human follicle-stimulating hormone receptor in hormone binding and receptor activation.

The follicle-stimulating hormone (FSH) receptor is a member of the glycoprotein hormone receptor subfamily of the seven-transmembrane receptor superfamily. These receptors have an extracellular N-terminal half of approximately 350 amino acids and a membrane-associated C-terminal half of approximately 350 amino acids. The N-terminal halves have the high affinity hormone binding site. On the other hand, the C-terminal half of the lutropin/choriogonadotropin receptor has the receptor activation site. However, little is known about the activation site and mechanism of the FSH receptor, although the existing evidence indicates crucial differences in the activation of the FSH receptor and the lutropin/choriogonadotropin receptor. As a first step to resolve this issue, we examined the upstream juxtamembrane five amino acids, Asp405-Ile406-His407-Thr408-Lys409, of the exoloop 1. Ala scan and multi-substitutions show that the five amino acid sequence is important for both hormone binding and receptor activation to induce cAMP synthesis, despite its short length. Specifically, His407 is important for high affinity hormone binding, whereas Asp405, Thr408, and Lys409 are crucial for receptor activation. The data suggest that the five amino acids may form a turn of helix that is an extension of the transmembrane helix 2. In this helical arrangement, Asp405, Thr408, and Lys409 are grouped to form a hydrophilic face of the helix, suggesting a correlation between this arrangement and receptor activation. In addition, the diverse and differential roles of the five amino acids indicate that high affinity hormone binding and receptor activation are discernible functions. These novel observations will be helpful for understanding the activation mechanism of the FSH receptor.

Amino Acid Sequence↗
PubMed1997

Determinants of chromatin disruption and transcriptional regulation instigated by the thyroid hormone receptor: hormone-regulated chromatin disruption is not sufficient for transcriptional activation.

Chromatin disruption and transcriptional activation are both thyroid hormone-dependent processes regulated by the heterodimer of thyroid hormone receptor and 9-cis retinoic acid receptor (TR-RXR). In the absence of hormone, TR-RXR binds to nucleosomal DNA, locally disrupts histone-DNA contacts and generates a DNase I-hypersensitive site. Chromatin-bound unliganded TR-RXR silences transcription of the Xenopus TRbetaA gene within a canonical nucleosomal array. On addition of hormone, the receptor directs the extensive further disruption of chromatin structure over several hundred base pairs of DNA and activates transcription. We define a domain of the TR protein necessary for directing this extensive hormone-dependent chromatin disruption. Particular TR-RXR heterodimers containing mutations in this domain are able to bind both hormone and their thyroid hormone receptor recognition element (TRE) within chromatin, yet are unable to direct the extensive hormone-dependent disruption of chromatin or to activate transcription. We distinguish the hormone-dependent disruption of chromatin and transcriptional activation as independently regulated events through the mutagenesis of basal promoter elements and by altering the position and number of TREs within the TRbetaA promoter. Chromatin disruption alone on a minichromosome is shown to be insufficient for transcriptional activation of the TRbetaA gene.

Amino Acid Sequence↗
PubMed2003

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer.

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.

Breast Neoplasms↗
PubMed1994

Clinical syndromes of hormone receptor mutations: hormone resistance and independence.

Clinical syndromes of hormone resistance or independence have baffled clinicians for decades. These syndromes sometimes result from mutations or deficiencies in enzymes that activate prohormones or from alterations in signal transduction proteins. The majority of these conditions, however, arise from abnormalities of hormone receptors. We describe examples of syndromes that result from genetic mutations or misexpression of steroid/thyroid hormone receptors, with a specific emphasis on thyroid and androgen resistance syndromes, and estrogen independence in breast cancer.

Animals↗
PubMed1998

Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies. A specific conformational change may be required for full-length receptor signaling.

Signal transduction by the growth hormone receptor (GHR) occurs through growth hormone (GH)-induced dimerization of two GHRs to form a trimeric complex. It is thought that dimerization alone is sufficient for signaling, since monoclonal antibodies (mAbs) against the extracellular domain of the GHR elicit proliferation of FDC-P1 cells transfected with a chimeric receptor comprising the extracellular domain of the GHR and the fibronectin and cytoplasmic domains of the murine granulocyte colony-stimulating factor receptor. We have screened 14 GHR mAbs for proliferative activity against characterized FDC-P1 and BaF-B03 cell lines stably expressing the full-length human, rabbit, or rat GHR, or the chimeric human GHR/granulocyte colony-stimulating factor receptor, and for transactivation of the c-fos promoter and STAT activation. With the chimeric receptor, eight mAbs were able to elicit proliferation, although there was no correlation between inhibition of hormone binding and agonist activity. In contrast, no mAbs were able to act as agonists with the full-length GHR FDC-P1 cell lines, although nine competed with GH for binding. A weak proliferative response was observed in the BaF-B03 cell lines with two of the mAbs (263 and 1C9), and the addition of anti-mouse F(ab)2 resulted in increased signaling in the hGHR BaF-B03 cell line to a plateau of 28 +/- 4% of the GH maximum for mAb 263. These data could indicate considerable stringency in the ability of mAbs to correctly dimerize the full-length GHR. However, the ability of mAb 263 to stimulate a mutant hGHR altered in the F'-G' loop of domain 2 was nearly abolished, concurrent with an increased affinity of this mAb for the receptor. Since the F'-G' loop undergoes a conformational change on GH binding and is necessary for full proliferative signaling, we propose that in addition to promoting receptor dimerization, mAb 263 may induce specific changes in receptor conformation similar to GH, which are required for the biological response.

Animals↗
PubMed2001

Isoform-specific transcriptional regulation by thyroid hormone receptors: hormone-independent activation operates through a steroid receptor mode of co-activator interaction.

Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors that play important roles in vertebrate homeostasis, differentiation, and development. T3Rs are synthesized as multiple isoforms that display tissue-specific expression patterns and distinct transcriptional properties. Most T3R isoforms associate with co-activator proteins and mediate transcriptional activation only in the presence of thyroid hormone. The pituitary-specific T3Rbeta-2 isoform departs from this general rule and is able to interact with p160 co-activators, and to mediate transcriptional activation in both the absence and presence of hormone. We report here that this hormone-independent activation is mediated by contacts between the unique N terminus of T3Rbeta-2 and an internal interaction domain in the SRC-1 (steroid receptor co-activator-1) and GRIP-1 (glucocorticoid receptor interacting protein 1) co-activators. These hormone-independent contacts between T3Rbeta-2 and the p160 co-activators are distinct in sequence and function from the LXXLL motifs that mediate hormone-dependent transcriptional activation and resemble instead a mode of co-activator recruitment previously observed only for the steroid hormone receptors and only in the presence of steroid hormone. Our results suggest that the transcriptional properties of the different T3R isoforms represent a combinatorial mixture of repression, antirepression, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome.

Amino Acid Sequence↗
PubMed2002

Distinct functions of photoreceptor cell-specific nuclear receptor, thyroid hormone receptor beta2 and CRX in one photoreceptor development.

PURPOSE: To clarify the functions of a specific subtype of thyroid hormone receptor (TR), TRbeta2, and photoreceptor cell-specific nuclear receptor (PNR) in the development of cone photoreceptors. METHODS: The expression of short (S)- and medium (M)-wavelength cone opsins was analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Northern blot analysis in mice without a functional PNR (rd7/rd7 mice), and levels of plasma thyroid hormones and expression of TRbeta2 were also examined. Concomitantly, by means of reporter assays, the roles of PNR and TRbeta2 in the S- and M-cone opsin expression were explored at the transcriptional level. RESULTS: In rd7/rd7 mice, an abnormal increase in cone photoreceptors was observed immediately before retinal maturation normally occurs. Although an increase in S-cone opsin in the retina was observed during and after retinal development, the expression of M-cone opsin expression was not perturbed during retinal maturation. Plasma concentrations of thyroid hormone and levels of TRbeta2 expression in the rd7/rd7 mouse retina over the developmental period were normal. Transcriptional studies demonstrated that TRbeta2, but not PNR, activated the M-cone opsin gene promoter function, while suppressing the S-cone opsin promoter function enhanced by CRX in a thyroid hormone-dependent manner. CONCLUSIONS: The results indicate that PNR may suppress proliferation of cone photoreceptor progenitor cells and that the regulation of S- and M-cone opsin gene expression is mediated by TRbeta2 and CRX, but not by PNR. Thus, our results partly disclosed the molecular mechanism of cone photoreceptor development, highlighting the distinct functions of PNR and TRbeta2.

Animals↗
PubMed1999

Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging.

Although previous studies have shown that cardiac myosin heavy chain (MHC) composition undergoes a switch from the alpha- to beta-isoform in the heart during adult aging, the underlying mechanisms responsible for this switch are unknown. Cardiac MHC gene expression is regulated, in part, by thyroid hormone responsive elements present in the regulatory control regions of the alpha- and beta-MHC genes. Age-associated changes in the expression of thyroid hormone receptors (THRs) and/or retinoid X receptors (RXRs), the heterodimeric partner for THRs, could explain the age-associated changes in MHC expression. Accordingly, we measured mRNA levels for the cardiac muscle MHCs and the rat THR and RXR genes in the left ventricles of Wistar rats at 2, 6, and 24 months of age. Although there were no significant changes in RXR alpha or RXR beta mRNA levels with age, both alpha 1 and alpha 2 THR mRNA levels decreased significantly between 2 and 6 months of age. During this same time period, the mRNA levels for alpha-MHC declined by more than half, whereas beta-MHC mRNA levels remained low and unchanged. On the other hand, between 6 and 24 months, when mRNA levels for beta-MHC increased and alpha-MHC continued to decrease, there was a significant decline in THR beta 1 and RXR gamma mRNA levels accompanied by a reduction in the THR beta 1 and RXR gamma protein levels. These data show a pattern of change that suggests that the decline in alpha-MHC gene expression may be biphasic and due to a decline in alpha 1 (and possibly alpha 2) THR levels between 2 and 6 months of age and a decline in THR beta 1 and RXR gamma levels at later stages. In contrast, the increase in beta-MHC gene expression was associated only with the changes in THR beta 1 and RXR gamma mRNA and protein levels.

Aging↗
PubMed1984

Homologous regulation of hormone receptors: luteinizing hormone increases its own receptors in cultured rat granulosa cells.

LH receptors in granulosa cells are essential for ovulation and luteinization of ovarian follicles. We have studied the possible role of LH to regulate its own receptors in vitro. Granulosa cells obtained from immature hypophysectomized estrogen-treated rats were primed with FSH for 2 days to induce LH receptors. The cells were then challenged with or without increasing doses of LH or hCG for an additional 2 days, and the concentration of LH receptors was measured by [125I]iodo-hCG binding. FSH-induced LH receptors in granulosa cells decreased to negligible levels in cultures without gonadotropins, while LH receptor numbers were further increased by LH or hCG in a biphasic manner. Maximal stimulation of LH receptor content was obtained with gonadotropin doses of 6, 10, and 2.5 ng/ml for rat LH, ovine LH, and hCG, respectively. In contrast, higher doses of the gonadotropins were less effective. LH stimulation of [125I]iodo-hCG-binding sites was associated with increases in the number of LH receptors, without changes in the Kd value (control, 1.22 +/- 0.22 X 10(-10) M; LH-treated, 2.55 +/- 0.55 X 10(-10) M). Also, the changes in LH receptor numbers were correlated with the responsiveness of granulosa cells to LH stimulation of cAMP production. LH and hCG did not affect overall granulosa cell protein content. However, treatment with cycloheximide, a protein synthesis inhibitor, decreased LH-induced receptors by 46%, suggesting the involvement of new protein synthesis. Thus, these studies have demonstrated that LH, like FSH, is capable of stimulating granulosa cell differentiation by inducing its own receptors. This serves as an interesting model for studies on the positive autoregulation of hormone receptors and explains the important role of LH during advanced stages of follicular maturation.

Animals↗
PubMed1995

Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer.

Retinoic acid (RA) is required for normal airway epithelial cell growth and differentiation both in vivo and in vitro. One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR beta) mRNA. Previous work established that many lung cancer cell lines and primary tumors display abnormal RAR beta mRNA expression, most often absence or weak expression of the RAR beta 2 isoform, even after RA treatment. Restoration of RAR beta 2 into RAR beta-negative lung cancer cell lines has been reported to inhibit tumorigenicity. Since RAR beta 2 inactivation may contribute to lung cancer, we have investigated the molecular mechanism of defective RAR beta 2 expression. Nuclear run-on assays and transient transfections with RAR beta 2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE). These defects cannot be complemented by RAR-retinoid X receptor cotransfection and can be separated into two types: (i) one affecting transcription from direct repeat RAREs, but not palindromic RAREs, and (ii) another affecting transcription from both types of RARE. Studies using chimeras between RAR alpha, TR alpha, and other transcription factors suggest the existence of novel RAR-thyroid hormone receptor AF-2-specific cofactors, which are necessary for high levels of transcription. Furthermore, these factors may be frequently inactivated in human lung cancer.

Adenovirus E1A Proteins↗