BACKGROUND: This Case Conference reviews the normal changes in thyroid activity that occur during pregnancy and the proper use of laboratory tests for the diagnosis of thyroid dysfunction in the pregnant patient. CASE: A woman in the 18th week of pregnancy presented with tachycardia, increased blood pressure, severe vomiting, increased total and free thyroid hormone concentrations, a thyroid-stimulating hormone (TSH) concentration within the reference interval, and an increased human chorionic gonadotropin (hCG) beta-subunit concentration. ISSUES: During pregnancy, normal thyroid activity undergoes significant changes, including a two- to threefold increase in thyroxine-binding globulin concentrations, a 30-100% increase in total triiodothyronine and thyroxine concentrations, increased serum thyroglobulin, and increased renal iodide clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy produces an overall increase in thyroid activity, which allows the healthy individual to remain in a net euthyroid state. However, both hyper- and hypothyroidism can occur in pregnant patients. In addition, two pregnancy-specific conditions, hyperemesis gravidarum and gestational trophoblastic disease, can lead to clinical hyperthyroidism. The normal changes in thyroid activity and the association of pregnancy with conditions that can cause hyperthyroidism necessitates careful interpretation of thyroid function tests during pregnancy. CONCLUSION: Assessment of thyroid function during pregnancy should be done with a careful clinical evaluation of the patient's symptoms as well as measurement of TSH and free, not total, thyroid hormones. Measurement of thyroid autoantibodies may also be useful in selected cases to detect maternal Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal consequences of maternal thyroid dysfunction. (+info)
Transcriptional anti-repression. Thyroid hormone receptor beta-2 recruits SMRT corepressor but interferes with subsequent assembly of a functional corepressor complex.
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Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors. Different T3R isoforms are expressed in a tissue-specific and developmentally regulated manner. The T3Ralpha-1, beta-0, and beta-1 isoforms typically repress target gene expression in the absence of hormone and activate transcription in the presence of hormone. Intriguingly, however, the T3Rbeta-2 isoform fails to repress, and instead is able to activate transcription in both the absence and presence of hormone. We investigated the molecular mechanism behind this absence of repression by T3Rbeta-2. Repression by T3Ralpha-1, beta-0, and beta-1 is mediated by the ability of these isoforms to physically recruit a SMRT/N-CoR corepressor complex. We determined that the unliganded T3Rbeta-2 also recruits the SMRT corepressor; in contrast to the alpha-1, beta-0, and beta-1 isoforms, however, the T3Rbeta-2 protein interacts not only with the C-terminal "receptor-interaction domain" of SMRT, but also makes additional contacts with the N-terminal "silencing domain" of the SMRT corepressor. These additional, T3Rbeta-2-specific contacts interfere with the subsequent association of SMRT with mSin3, a crucial second subunit of the corepressor holo-complex. Our results suggest that T3Rbeta-2 regulates transcription through a novel anti-repression mechanism, recruiting SMRT, but preventing the subsequent formation of a functional corepressor complex. (+info)
Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription.
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A contemporary view of hormone action at the transcriptional level requires knowledge of the transcription factors including the hormone receptor that may bind to promoters or enhancers, together with the chromosomal context within which these regulatory proteins function. Nuclear receptors provide the best examples of transcriptional control through the targeted recruitment of large protein complexes that modify chromosomal components and reversibly stabilize or destabilize chromatin. Ligand-dependent recruitment of transcriptional coactivators destabilizes chromatin by mechanisms including histone acetylation and contacts with the basal transcriptional machinery. In contrast, the recruitment of corepressors in the absence of ligand or in the presence of hormone antagonists serves to stabilize chromatin by the targeting of histone deacetylases. Both activation and repression require the action of other chromatin remodeling engines of the switch 2/sucrose non-fermentable 2 (SWI2/SNF2) class. Here we summarize this information and integrate hormone action into a chromatin context. (+info)
Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11).
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Although most extraskeletal myxoid chondrosarcomas (EMC) are cytogenetically characterized by the translocation t(9;22)(q22;q12), another subset has recently been identified carrying a t(9;17)(q22;q11). Whereas the t(9;22) is known to result in fusion of the CHN (TEC) gene from 9q22 with the EWS gene from 22q12, creating a chimeric EWS/CHN, the genes involved in the t(9;17) of EMC are unknown. We examined two EMC with t(9;17)(q22;q11) and found that the CHN gene was recombined with the RBP56 gene from 17q11 to generate a chimeric RBP56/CHN. RBP56 has not previously been shown to be involved in tumorigenesis but it encodes a putative RNA-binding protein similar to the EWS and FUS (TLS) proteins known to play a pathogenetic role in several sarcomas. The presence of the RBP56/CHN chimeric gene in EMC with t(9;17)(q22;q11) shows that the N-terminal parts of EWS and RBP56 have similar oncogenic potential making them pathogenetically equivalent in oncoproteins arising from fusions with certain transcription factors. (+info)
Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma.
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A proportion of extraskeletal myxoid chondrosarcomas (EMC) have been shown to have a characteristic translocation t(9;22)(q22;q12) involving the EWS gene at 22q12 and the CHN orphan nuclear receptor gene at 9q22. This translocation appears to be largely specific for EMC, but has not been detected in all such tumours. We report here a case of EMC with a t(9;17)(q22;q11.2) as the sole chromosome abnormality. We have determined that the translocation results in the fusion of the entire coding region of CHN to the N-terminal transactivation domain of RBP56/hTAFII68. This is the first report of a translocation involving RBP56/hTAFII 68, a protein with sequence homology to both EWS and TLS/FUS. The involvement of RBP56/hTAFII68 may explain some unusual features of the tumour. (+info)
Effects of T3R alpha 1 and T3R alpha 2 gene deletion on T and B lymphocyte development.
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Thyroid hormones bind to several nuclear receptors encoded by T3R alpha and T3R beta genes. There is now accumulating evidence that thyroid hormones act on the immune system. Indeed, mice deficient for thyroid hormones show a reduction in lymphocyte production. However, the mechanisms involved and, in particular, the role of the different thyroid hormone receptors in lymphocyte development have not been investigated. To address that question, we have studied lymphocyte development in mice deficient for the T3R alpha 1 and T3R alpha 2 gene products. A strong decrease in spleen cell numbers was found compared with wild-type littermates, B lymphocytes being more severely affected than T lymphocytes. A significant decrease in splenic macrophage and granulocyte numbers was also found. In bone marrow, a reduction in CD45+/IgM- pro/pre-B cell numbers was found in these mice compared with wild-type littermates. This decrease seems to result from a proliferation defect, as CD45+/IgM- cells incorporate less 5-bromo-2'-deoxyuridine in vivo. To define the origin of the bone marrow development defect, chimeric animals between T3R alpha-/- and Rag1-/- mice were generated. Results indicate that for B cells the control of the population size by T3R alpha 1 and T3R alpha 2 is intrinsic. Altogether, these results show that T3R alpha 1 or T3R alpha 2 gene products are implicated in the control of the B cell pool size. (+info)
Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily.
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The androgen receptor (AR) binds to androgen response elements and regulates target genes via a mechanism involving coregulators. Here we demonstrate that the AR can interact with the testicular orphan receptor-4 (TR4) and function as a repressor to down-regulate the TR4 target genes by preventing the TR4 binding to its target DNA. Interestingly, the heterodimerization of AR and TR4 also allows TR4 to repress AR target gene expression. Simultaneous exposure to both receptors therefore could result in bidirectional suppression of their target genes. Together, these data demonstrate that the coupling of two different receptors, through the heterodimerization of AR and TR4, is a unique signaling pathway in the steroid receptor superfamily, which may facilitate further understanding of the complicated androgen action in prostate cancer or libido. (+info)
Molecular determinants of nuclear receptor-corepressor interaction.
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Retinoic acid and thyroid hormone receptors can act alternatively as ligand-independent repressors or ligand-dependent activators, based on an exchange of N-CoR or SMRT-containing corepressor complexes for coactivator complexes in response to ligands. We provide evidence that the molecular basis of N-CoR recruitment is similar to that of coactivator recruitment, involving cooperative binding of two helical interaction motifs within the N-CoR carboxyl terminus to both subunits of a RAR-RXR heterodimer. The N-CoR and SMRT nuclear receptor interaction motifs exhibit a consensus sequence of LXX I/H I XXX I/L, representing an extended helix compared to the coactivator LXXLL helix, which is able to interact with specific residues in the same receptor pocket required for coactivator binding. We propose a model in which discrimination of the different lengths of the coactivator and corepressor interaction helices by the nuclear receptor AF2 motif provides the molecular basis for the exchange of coactivators for corepressors, with ligand-dependent formation of the charge clamp that stabilizes LXXLL binding sterically inhibiting interaction of the extended corepressor helix. (+info)