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C A Meier

Publications and source records attributed to C A Meier.

53 records · Page 3Linked to original sources
PubMed1995

[Molecular endocrinology of thyroid diseases].

Over the last decade it has become possible to investigate the molecular basis of functional and neoplastic thyroid diseases, leading to the elucidation of various genetic defects at the level of the pituitary, thyroid and target organs. Mutations in either the pituitary-specific transcription factor Pit-1 or its target gene, TSH beta, lead to rare forms of hereditary congenital hypothyroidism. However, somatic mutations in thyroid epithelial cells causing an increase in hormone production and/or cellular proliferation are much more frequent. Nearly 50% of all toxic adenomas were shown to harbour activating mutations in either the TSH-receptor or certain G-proteins. In contrast, follicular and papillary thyroid malignancies are associated with mutations in the ras and ret genes respectively. Intriguingly, different mutations and rearrangements in the ret gene were shown to cause medullary thyroid cancer and MEN2 as well as to be specifically associated with papillary thyroid cancer. In contrast, mutations in thyroid-specific genes, such as thyroid peroxidase and thyroglobulin, causing congenital hypothyroidism are extremely rare. Besides the molecular abnormalities at the pituitary and thyroidal level leading to altered hormone secretion, genetic defects impairing thyroid hormone action at the target level also occur. Specifically, mutations in one of the thyroid hormone receptor genes (the proto-oncogene c-erbA beta) were shown to cause the autosomal dominant syndrome of resistance to thyroid hormone. The quest for a better understanding of the molecular defects in the pituitary-thyroid axis has led to the cloning of some of the key proteins, which can now be used for diagnostic purposes in vivo and in vitro. The use of recombinant thyroid peroxidase and TSH-receptor proteins has made possible the development of more sensitive and specific in vitro assays for autoantibodies. In addition, recombinant TSH was recently shown to be effective in stimulating radioiodine uptake in patients with residual differentiated thyroid cancer who remained on suppressive thyroid hormone therapy. Recombinant human TSH may therefore become a convenient diagnostic tool in the follow-up of patients with thyroid cancer by allowing for thyroglobulin measurements and radioiodine scanning without the need for the patient to become hypothyroid.

DNA-Binding Proteins↗
PubMed1995

Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat.

The peroxisome proliferator-activated receptors (PPAR) and thyroid hormone receptors (TR) are members of the nuclear receptor superfamily, which regulate lipid metabolism and tissue differentiation. In order to bind to DNA and activate transcription, PPAR requires the formation of heterodimers with the retinoid X receptor (RXR). In addition to activating transcription through its own response elements, PPAR is able to selectively down-regulate the transcriptional activity of TR, but not vitamin D receptor. The molecular basis of this functional interaction has not been fully elucidated. By means of site-directed mutagenesis of hPPAR alpha we mapped its inhibitory action on TR to a leucine zipper-like motif in the ligand binding domain of PPAR, which is highly conserved among all subtypes of this receptor and mediates heterodimerization with RXR. Replacement of a single leucine by arginine at position 433 of hPPAR alpha (L433R) abolished heterodimerization of PPAR with RXR and consequently its trans-activating capacity. However, a similar mutation of a leucine residue to arginine at position 422 showed no alteration of heterodimerization, DNA binding, or transcriptional activation. The dimerization deficient mutant L433R was no longer able to inhibit TR action, demonstrating that the selective inhibitory effect of PPAR results from the competition for RXR as well as possibly for other TR-auxiliary proteins. In contrast, abolition of DNA binding by a mutation in the P-box of PPAR (C122S) did not eliminate the inhibition of TR trans-activation, indicating that competition for DNA binding is not involved. Additionally, no evidence for the formation of PPAR:TR heterodimers was found in co-immunoprecipitation experiments. In summary, we have demonstrated that PPAR selectively inhibits the transcriptional activity of TRs by competition for RXR and possibly non-RXR TR-auxiliary proteins. In contrast, this functional interaction is independent of the formation of PPAR:TR heterodimers or competition for DNA binding.

Amino Acid Sequence↗
PubMed1995

Quantitation of beta 1 triiodothyronine receptor mRNA in human tissues by competitive reverse transcription polymerase chain reaction.

Thyroid hormones act by binding to nuclear receptor proteins, the thyroid hormone receptors (TR) alpha and beta. Data from cell culture and animal studies indicate that TR expression may be regulated to modulate target organ responsiveness to thyroid hormone. To investigate whether such adaptive changes in TR expression occur in humans, we determined the mRNA levels of the hTR beta 1 in various thyroid states. Patients with overt hypo- or hyperthyroidism were enrolled in the study. Total RNA was isolated from peripheral blood mononuclear cells and hTR beta 1 mRNA levels determined by quantitative competitive reverse transcription PCR. For comparison, hTR beta 1 mRNA levels were determined in lymphocytes and normal thyroid tissue of euthyroid patients. Human TR beta 1 mRNA levels in lymphocytes were 1.8 +/- 0.4, 1.9 +/- 0.5, 1.1 +/- 0.4 10(-18) mol/microgram RNA in hypo-, eu- and hyperthyroid patients, respectively, corresponding to an estimated 0.5 - 2 molecules per cell. Although the mean hTR beta 1 mRNA levels were 40% lower in hyperthyroid than in euthyroid subjects, this difference did not reach statistical significance. Similar levels of hTR beta 1 mRNA levels were detected in thyroid gland from euthyroid patients. In summary, we developed an assay for the quantitative determination of hTR beta 1 mRNA levels in small human tissue samples, containing as little as 50 ng of total RNA. Absolute hTR beta 1 mRNA levels are very low with an estimated one molecule of mRNA being present in a mononuclear blood cell or thyrocyte. No up-regulation of hTR beta 1 was seen in hypothyroid relative to euthyroid patients. However, there is a non-significant trend towards a down-regulation of hTR beta 1 mRNA levels in hyperthyroid patients.

Adolescent↗
PubMed1995

Modulation of thyroid hormone action by mutant thyroid hormone receptors, c-erbA alpha 2 and peroxisome proliferator-activated receptor: evidence for different mechanisms of inhibition.

Thyroid hormone action is not only determined by hormone availability, but also by target organ sensitivity. A dominant negative interaction is known to occur between thyroid hormone receptors (TRs) and the non-ligand binding splicing variant c-erbA alpha 2 as well as mutant TR beta 1 from kindreds with resistance to thyroid hormone. We compared the inhibitory effect of naturally occurring mutant hTR beta 1, artificially created hTR alpha 1 mutants, c-erbA alpha 2 and the human peroxisome proliferator-activated receptor (hPPAR) on three prototypic T3-response elements (TREs), TRE-PAL, DR + 4 and TRE-LAP. The inhibitory effect of mutant hTR alpha 1 and beta 1 occurred only on TRE-LAP and to a minor degree on DR + 4 when equimolar ratios of mutant/wildtype receptor were present. In contrast, the c-erbA alpha 2 splicing variant and the hPPAR inhibited TR action on all three TREs. Gel mobility shift experiments in the presence of T3 showed increased binding of mutant hTR alpha 1 and beta 1 only to TRE-LAP compared to the binding of wildtype hTRs, thereby explaining their TRE-selective dominant negative potency. Contrarily, equal amounts of c-erbA alpha 2 or hPPAR protein did not bind to either of the three response elements even in the presence of RXR. Since the TR:RXR heterodimers were only partially displaced from DNA in the presence of excess amounts of c-erbA alpha 2, it is likely that the TRE-unspecific dominant negative action of c-erbA alpha 2 is due in part to competition for DNA-binding and for TR-auxiliary proteins. In contrast, equimolar amounts of hPPAR completely inhibited the DNA-binding of hTR beta 1:RXR heterodimers, but not of TR:TR homodimers, suggesting that hPPAR has a higher RXR-binding affinity and is therefore a potent competitor for intranuclear RXR. Since thyroid hormones and peroxisome proliferators regulate in part a similar subset of target genes involved in fatty acid metabolism, these results suggest the possibility of cross-talk among the thyroid hormone and peroxisome proliferator signalling pathways. In summary, the results suggest that thyroid hormone action can be modulated by at least three different mechanisms: (i) increased binding of mutant hTRs to specific TREs; (ii) efficient competition for limiting amounts of RXR through the preferential formation of hPPAR:RXR, rather than TR:RXR heterodimers; and (iii) competition for binding to DNA and to auxiliary proteins other than RXR in the case of c-erbA alpha 2.

DNA↗
PubMed1994

Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study).

Current diagnostic studies [radioiodine uptake and serum thyroglobulin (Tg) levels] for residual or metastatic thyroid tissue in patients with differentiated thyroid carcinoma require a hypothyroid status necessary for adequate endogenous TSH stimulation. However, almost all patients have symptoms of clinical hypothyroidism during this period. As shown in the present study, recombinant human TSH (rhTSH) allows stimulation of 131I uptake and Tg release from residual thyroid tissue in euthyroid patients. To assess safety, dosage, and preliminary efficacy, comparison was made of the stimulation of 131I uptake and Tg release after rhTSH administration and after T3 withdrawal in 19 patients after a recent thyroidectomy for differentiated thyroid carcinoma. Various doses (10-40 U) of rhTSH were injected im for 1-3 days in patients receiving suppressive doses of T3. Twenty-four hours after the last dose of rhTSH, 1-2 mCi 131I were administered, followed by a neck and whole body scan 48 h later. After discontinuing T3 for a median period of 19 days (range, 15-28), endogenous serum TSH levels were markedly elevated, and the patients were given a second dose of 131I and rescanned 48 h later. The injections of rhTSH were tolerated well. No major adverse effects were reported; nausea was reported in 3 (16%) and vomiting in 1 of the patients treated with high doses. The quality of life, as measured by two psychometric scales, was far better during rhTSH treatment than after T3 withdrawal. The peak levels of serum TSH (mean +/- SD) after a single dose of 10, 20, or 30 U were 127 +/- 19, 309 +/- 156, and 510 +/- 156 mU/L, respectively, and occurred 2-8 h after injection. Twenty-four hours after the injection, TSH levels decreased to 83 +/- 31, 173 +/- 73, and 463 +/- 148 mU/L in these treatment groups, respectively. The quality of the thyroid scans and the number of sites of abnormal 131I uptake were similar after rhTSH treatment and in the hypothyroid scans in 12 (63%) patients. Two additional sites of uptake in the chest and one in the thyroid bed, not visible on the hypothyroid scans, were identified in 3 (16%) patients after rhTSH. In 1 patient a focus of uptake was better visualized after rhTSH than after withdrawal. In 3 (16%) other patients, 1 lesion in the chest and 2 in the neck were seen only after T3 withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Interindividual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests.

OBJECTIVE: We investigated interindividual differences in the shape, slope and setpoint of the pituitary-thyroid axis (PTA) in normal persons. Based on these physiological data we propose a novel bivariate concept for the interpretation of thyroid function tests which is less biased by interindividual differences in the PTA than the currently used univariate approach. DESIGN: In two separate trials (A and B), healthy volunteers were given small, increasing doses of T3 (7.5-45 micrograms/day orally) over 5 days. The regulation characteristics of the individual PTAs and the effects of age and gender were assessed by general linear regression models. In addition, serum samples were collected from normal persons to establish the proposed bivariate approach for the interpretation of thyroid function tests. SUBJECTS: The regulatory characteristics of the PTA were determined in a total of 21 normal volunteers (eight females, 13 males; age 24-49 years). Single blood samples were collected from 257 normal volunteers. The participants had no history of pituitary or thyroid disease. MEASUREMENTS: Free and total thyroid hormone and TSH concentrations were determined in the serum. All samples from one person were analysed in the same assay in duplicate. RESULTS: A log-linear relationship between T3 and TSH was found to describe best the individual PTA (multiple r = 0.96). However, significant differences in the setpoint (P < 0.001) and to a lesser degree in the slope (P < or = 0.05) of the PTA were detected; this variability was not dependent on age or gender. Since these findings invalidate the assumptions on which the current univariate interpretation of thyroid function tests is based, we propose a novel model for the evaluation of thyroid function tests derived from the experimentally determined shape and average slope of the PTA. CONCLUSIONS: The presence of significant age and gender-independent interindividual variations in the setpoint of the pituitary-thyroid axis raises conceptual problems with the current approach for interpreting thyroid function tests. An easy to use graphical bivariate representation of the normal ranges for thyroid function tests is presented and exemplified by the thyroid hormone and TSH measurements in a large reference population. This concept should improve the diagnostic accuracy in the borderline-normal, and particularly subclinical hypothyroid region of these hormone measurements.

Adult↗
PubMed1993

Interaction of human beta 1 thyroid hormone receptor and its mutants with DNA and retinoid X receptor beta. T3 response element-dependent dominant negative potency.

Mutations in the human beta thyroid hormone receptor (h-TR beta) gene are associated with the syndrome of generalized resistance to thyroid hormone. We investigated the interaction of three h-TR beta 1 mutants representing different types of functional impairment (kindreds ED, OK, and PV) with different response elements for 3,3',5-triiodothyronine (T3) and with retinoid X receptor beta (RXR beta). The mutant receptors showed an increased tendency to form homodimers on a palindromic T3-response element (TREpal), a direct repeat (DR + 4), and an inverted palindrome (TRElap). On TRElap, wild type TR binding was decreased by T3, while the mutant receptors showed a variably decreased degree of dissociation from TRElap in response to T3. The extent of dissociation was proportional to their T3 binding affinities. RXR beta induced the formation of h-TR beta 1:RXR beta heterodimers equally well for mutants and the wild type h-TR beta 1 on these T3 response elements. However, the T3-dependent increase in heterodimerization with RXR beta was absent or reduced for the mutant TRs. Transient transfection studies indicated that the dominant negative potency was several-fold more pronounced on the TRElap as compared to TREpal or DR + 4. In CV-1 and HeLa cells, transfection of RXR beta could not reverse the dominant negative action. These results demonstrate that the binding of mutant h-TRs to DNA, as well as their dominant negative potency, are TRE dependent. In addition, competition for DNA binding, rather than for limiting amounts of RXR beta, is likely to mediate the dominant negative action.

Animals↗
PubMed1992

Variable transcriptional activity and ligand binding of mutant beta 1 3,5,3'-triiodothyronine receptors from four families with generalized resistance to thyroid hormone.

Mutations in the gene encoding the human beta 1 T3 receptor (hTR beta 1) have been associated with generalized resistance to thyroid hormone (GRTH). We measured the T3-binding affinity and transcriptional regulatory capacity of the mutant hTR beta 1 from four unrelated kindreds with GRTH. These mutations are contained in different functional regions of the ligand-binding domain. The T3 affinity of the mutant receptors correlated well with the degree of impairment of their trans-activating function in a transient cotransfection system in HeLa cells; two mutant receptors with undetectable ligand affinity showed no transcriptional activity, whereas the two other mutants characterized by a 2- and 5-fold reduction in T3 affinity required 5- and 15-fold higher T3 concentrations for half-maximal activity in the cotransfection assay, respectively. All of the mutant hTR beta 1s were able to inhibit the function of transfected normal hTR beta 1 and endogenous retinoic acid receptor in activating a palindromic positive T3 response element (TRE). In the partially functional mutants this dominant negative effect could be completely reversed by increased T3 concentrations. The dominant negative potency did not depend on the type of TRE used; mutant hTR beta 1s were able to inhibit normal receptor function to the same degree on a dimer-permissive palindromic TRE as on a nondimer-permissive inverted repeat of two identical half-sites separated by five spacer bases. However, the dominant negative potency was dependent on the absolute amount of receptor expression vector transfected. The expression of normal and mutant hTR beta 1 was assessed by immunocytochemistry. The hTR beta 1 protein levels in HeLa cells paralleled the amount of transfected expression vector. Moreover, all the mutant receptors were properly expressed in the nuclei of the transfected cells. These data suggest that different mutations in the ligand-binding domain of the human hTR beta 1 result in a variable degree of functional impairment, which may partially explain the phenotypic differences between kindreds with GRTH. Our findings suggest that competition for binding to the TRE and possibly the binding of limiting accessory factors may be more important in mediating the dominant negative effect than the formation of normal/mutant T3 receptor dimers.

Base Sequence↗
PubMed1991

Effect of hypothyroidism and thyroid hormone replacement on the level of protein kinase C and protein kinase A in rat liver.

We investigated the influence of the thyroid hormone status on the levels of protein kinases C (PKC) and A (PKA) in the soluble fraction of rat liver. The immunodetectable PKC level in hypothyroid liver was elevated 7.7-fold, whereas the phorbol-ester binding capacity and the immunodetectable alpha-PKC level were increased 2.4- and 2.6-fold, respectively. Conversely, in hypothyroid livers the abundance of the regulatory type I and the catalytic subunits of PKA were lowered to 42% of the euthyroid level as determined by immunoblotting and by measuring the substrate specific phosphorylation rate of PKA. These changes in the PKC and PKA levels were reversible upon treatment with 0.5 microgram T4/100 g body weight for 2-21 days. The thyroid state dependent alterations in hepatic PKC and PKA levels may be responsible for the known changes in the response of hepatocytes to other hormonal stimuli in hypothyroidism.

Animals↗
PubMed1991

Hypothyroidism and thyroxin substitution affect the n-3 fatty acid composition of rat liver mitochondria.

The effects of hypothyroidism and of daily treatment for up to 21 days with thyroxin (T4, 0.5 micrograms/100 g body weight) on the fatty acid composition of total lipid, phosphatidylethanolamine, and phosphatidylcholine of rat liver mitochondria were studied. The fatty acid compositions of hypothyroid and euthyroid (control) rats of similar age were compared. The n-6 and n-3 polyunsaturated fatty acids (PUFA) were affected differently by the hypothyroid state. The levels of linoleic (18:2n-6), gamma-linolenic (18:3n-6) and dihomo-gamma-linolenic acids (20:3n-6) were higher in hypothyroid rats than in controls, while the level of arachidonic acid (20:4n-6) was lower, which suggests an impairment of the elongase and desaturase activities. The n-3 polyunsaturated fatty acids, eicosapentaenoic (EPA, 20:5n-3) and docosapentaenoic (22:5n-3) acids, were higher in hypothyroid rats, whereas the linolenic acid (18:3n-3) content remained constant. The level of docosahexaenoic acid (DHA, 22:6n-3) was dramatically decreased in hypothyroid rats, while the levels of C22 n-6 fatty acids were unchanged. The differences were probably due to the competition between n-3 and n-6 PUFA for desaturases, elongases and acyltransferases. When hypothyroid rats were treated with thyroxin, the changes induced by hypothyroidism in the proportions of n-6 fatty acids were rapidly reversed, while the changes in the n-3 fatty acids were only partially reversed. After 21 days of thyroxin treatments, the DHA content was only half as high in hypothyroid rats than in euthyroid rats. These results suggest that the conversion of 18:2n-6 to 20:4n-6 is suppressed in the hypothyroid state which favors the transformation of 18:3n-3 to 20:5n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Comparison of 99Tcm-labelled MDP and DMAD bone scanning agents in patients with advanced breast cancer.

The detection of focal pathology on a bone scan is dependent on the contrast between uptake in a lesion compared with the affinity of the scanning agent for the surrounding normal bone. Dimethyl-amino diphosphonate (DMAD) has a relatively low uptake in normal bone compared with methylene diphosphonate (MDP). We have compared the bone scan appearance with MDP and DMAD in 11 patients with multiple bone metastases from breast cancer. The median time between scans was 7 days (range 6 to 14). In two patients additional lesions were identified on the DMAD scan. No additional lesions were visible on the MDP scans. In five patients some lesions were visualized more clearly with DMAD and others with MDP. In six patients no differences were seen. Anatomical resolution was generally less clear with DMAD and precise anatomical localization was sometimes impossible. We have demonstrated superior lesion detection with DMAD. The clinical value of this for the detection of early relapse of disease in the skeleton requires further study.

Bone Neoplasms↗
PubMed1984

[Temporal dynamics of spectral EEG parameters during nocturnal sleep in healthy adults].

We recorded all-night sleep EEG's of six healthy male volunteers (age 23 to 29 years) from F3, F4, P3, P4, 01, 02, T3, T4 to Cz as reference electrode. Power and coherence spectra were calculated for ten frequency bands from 0-30 cps. We examined their changes through the different cycles of all sleep stages. In general there was a decrease in power as well as in coherence from the 1st to the 4th cycle of the different sleep stages with some variations depending on frequency and derivation. The highest power was most often in the 1st cycle in stages REM, 2, 3 and 4, whereas in stage 1 it was most often in the 2nd cycle. The trends in power from the 1st to the 4th cycle were similar for stages REM and 2 with a power decrease from the 1st to the 2nd cycle. In stage 1 there was most often a power increase between these two cycles. Coherence maxima were for stages REM, 1, 2 and 3 most often in the 1st cycle, for stage 4 most often in the 2nd cycle. The coherence trends were similar for stages 1 and 2 with a decrease most often from the 1st to the 2nd cycle. In stage REM the decline was more constantly found from the 2nd to the 3rd cycle. The power trends were more consistent than the coherence trends. We found more often similar power changes from the 1st to the 4th cycle of a specific sleep stage than similar coherence changes.

Adult↗
PubMed1983

Spectral analysis of all-night sleep EEG in healthy adults.

Power and coherence spectra were computed from all-night sleep EEG records in 6 healthy adult subjects. Derivations were from F3, F4, P3, P4, O1, O2, T3, and T4 to the vertex (Cz). Records were conventionally scored into sleep stages. Average power per sleep stage was maximal at frequencies 0.4-6 c/s in stage 4, at 6-10 c/s in either stage 3 or stage 4, at 12-14 c/s in stage 2 and at 14-30 c/s in stage 1. The average power range from highest values in the lowest frequency band to lowest values in the highest frequency band showed marked differences between sleep stages: It was lowest (12-14 dB) in stage 1, followed by stage 2 (20-22 dB), and stage 3 (16-28 dB), and largest in stage 4 (29-32 dB). REM sleep (15-16 sB) was between stage 1 and 2. The waking state showed an average power range of 11-15 dB. Alpha power at 8-10 c/s in occipital and parietal leads was remarkably constant during sleep, i.e. independent of sleep stage. Coherence showed maximal values at 2-8 c/s in REM sleep, at 8-12 c/s in stage 4, at 12-17 c/s in either stage 3 or 4, and at 17-30 c/s again in stage REM. There was significant coherence increase at 2-8 and 17-30 c/s from NREM to REM sleep, most pronounced between parietal to vertex derivations. Overall coherence between both occipital-to-vertex, or between occipital and parietal-to-vertex derivations, was essentially higher than in the other derivations. The results, essentially, give a comprehensive phenomenology of the dynamic spectral structure of all-night sleep EEG. They suggest that the different brain states during sleep (e.g. stage 1 NREM vs. REM) which are associated with different functions (e.g. hypnagogic hallucinations vs. dreams) differ in EEG spectral parameters if coherence is considered. Likewise, they suggest that studies of automatic sleep staging based exclusively on EEG spectral parameters appear promising.

Adult↗
PubMedDate not supplied

Lack of loss of heterozygosity at the c-erbA beta locus in gastrointestinal tumors.

The cellular homologues of the viral oncogene c-erbA encode for the nuclear thyroid hormone receptor c-erbA (TR). The gene for the human TR beta subtype is located on chromosome 3p24, and a loss of heterozygosity around this region has been reported in breast and small cell lung cancers, suggesting that TR beta might act as a tumor suppressor gene. In the present study, we used PCR-based restriction fragment length polymorphisms to examine the 3p24 region of 19 patients with gastrointestinal tumors for loss of heterozygosity (LOH). Interestingly, only 1 of the patients had an LOH at this locus, while 4 patients had a microdeletion of both alleles in the 3p24 region. These results suggest that, in contrast to previous reports on lung and breast cancers, a loss of heterozygosity of the TR locus at 3p24 is a rare event. A critical review of the literature, however, suggests, that some of the earlier studies have used markers whose location is only imprecisely mapped and may hence point to a tumor suppressor gene candidate other than TR beta. However, a selective microdeletion of both alleles was detected in the tumors of 4 of the 19 patients, indicating that this region on chromosome 3p may be genetically unstable in gastrointestinal tumors.

Aged↗
PubMedDate not supplied

Regulation of gene expression by nuclear hormone receptors.

Steroids and thyroid hormones, as well as vitamin D, retinoids and some nutrient metabolites (fatty acids, prostaglandins, farnesol metabolites) act by binding to members of the zinc-finger containing superfamily of nuclear hormone receptors. These receptor proteins bind directly to specific DNA recognition sequences (hormone response elements) in the promoter region of target genes, resulting in the alteration of the transcription initiation rate. While the principle of action of these receptors appears to be quite simple, the promiscuous behavior of some members of this family as well as cross-talk with other signaling systems result in an intricate regulatory network with distinct particularities for each receptor type. Specific areas of current interest in nuclear receptor research are: (i) the mechanisms for target gene specificity, which occur at the level of receptor expression, ligand metabolism and/or DNA sequence; (ii) cross-talk with other signaling systems resulting in the modulation of the transcriptional activity of the ligand-activated receptor through phosphorylation and/or heterodimerization with shared nuclear factors; and (iii) the discovery of novel agonistic and antagonistic ligands for established and orphan nuclear receptors. Recent insights through screening strategies for putative ligands, the cloning of co-activator proteins, as well as the characterization of human and animal models with germline and somatic mutations in nuclear receptors have resulted in important insights into some of the above questions, which are fundamental for a better understanding of the role of these hormone-activated transcription factors during development and cell differentiation.

Gene Expression Regulation↗