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Zhang XY Kaneshige M Kamiya Y Kaneshige K McPhie P Cheng SY 《Molecular endocrinology (Baltimore, Md.)》2002,16(9):2077-2092
Mutations in the thyroid hormone receptor beta gene (TRbeta) cause resistance to thyroid hormone (RTH). Genetic analyses indicate that phenotypic manifestation of RTH is due to the dominant negative action of mutant TRbeta. However, the molecular mechanisms underlying the dominant negative action of mutants and how the same mutation results in marked variability of resistance in different tissues in vivo are not clear. Here we used a knock-in mouse (TRbetaPV mouse) that faithfully reproduces human RTH to address these questions. We demonstrated directly that TRbeta1 protein was approximately 3-fold higher than TRalpha1 in the liver of TRbeta(+/+) mice but was not detectable in the heart of wild-type and TRbetaPV mice. The abundance of PV in the liver of TRbeta(PV/PV) was more than TRbeta(PV/+) mice but not detectable in the heart. TRalpha1 in the liver was approximately 6-fold higher than that in the heart of wild-type and TRbetaPV mice. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed not only with TR isoforms for binding to thyroid hormone response elements (TRE) but also competed with TR for the retinoid X receptors in binding to TRE. These competitions led to the inhibition of the thyroid hormone (T(3))-positive regulated genes in the liver. In the heart, however, PV was significantly lower and thus could not effectively compete with TRalpha1 for binding to TRE, resulting in activation of the T(3)-target genes by higher levels of circulating thyroid hormones. These results indicate that in vivo, differential expression of TR isoforms in tissues dictates the dominant negative activity of mutant beta receptor, thereby resulting in variable phenotypic expression in RTH. 相似文献
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Weiss RE Korcarz C Chassande O Cua K Sadow PM Koo E Samarut J Lang R 《American journal of physiology. Endocrinology and metabolism》2002,283(3):E428-E435
We investigated the effect of thyroid hormone (TH) receptor (TR)alpha and -beta isoforms in TH action in the heart. Noninvasive echocardiographic measurements were made in mice homozygous for disruption of TRalpha (TRalpha(0/0)) or TRbeta (TRbeta(-/-)). Mice were studied at baseline, 4 wk after TH deprivation (using a low-iodine diet containing propylthiouracil), and after 4-wk treatment with TH. Baseline heart rates (HR) were similar in wild-type (WT) and TRalpha(0/0) mice but were greater in TRbeta(-/-) mice. With TH deprivation, HR decreased 49% in WT and 37% in TRbeta(-/-) mice and decreased only 5% in TRalpha(0/0) mice from baseline, whereas HR increased in all genotypes with TH treatment. Cardiac output (CO) and cardiac index (CI) in WT mice decreased (-31 and -32%, respectively) with TH deprivation and increased (+69 and +35%, respectively) with TH treatment. The effects of CO and CI were blunted with TH withdrawal in both TRalpha(0/0) (+8 and -2%, respectively) and TRbeta(-/-) mice (-17 and -18%, respectively). Treatment with TH resulted in a 64% increase in LV mass in WT and a 44% increase in TRalpha(0/0) mice but only a 6% increase in TRbeta(-/-) mice (ANOVA P < 0.05). Taken together, these data suggest that TRalpha and TRbeta play different roles in the physiology of TH action on the heart. 相似文献
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Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone
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Ying H Furuya F Willingham MC Xu J O'Malley BW Cheng SY 《Molecular and cellular biology》2005,25(17):7687-7695
Mutations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRbetaPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling. 相似文献
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Kinugawa K Jeong MY Bristow MR Long CS 《Molecular endocrinology (Baltimore, Md.)》2005,19(6):1618-1628
Alterations in TR [thyroid hormone (TH) receptor]1 isoform expression have been reported in models of both physiologic and pathologic cardiac hypertrophy as well as in patients with heart failure. In this report, we demonstrate that TH induces hypertrophy as a direct result of binding to the TRalpha1 isoform and, moreover, that overexpression of TRalpha1 alone is also associated with a hypertrophic phenotype, even in the absence of ligand. The mechanism of TH and TRalpha1-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor beta-activated kinase (TAK1) and p38. Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. These findings refine our previous observations on TR expression in the hypertrophied and failing heart and suggest that manipulation of thyroid hormone signaling in an isoform-specific manner may be a relevant therapeutic target for altering the pathologic myocardial program. 相似文献
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The timing of oligodendrocyte development is regulated by thyroid hormone (TH) in vitro and in vivo, but it is still uncertain which TH receptors mediate this regulation. TH acts through nuclear receptors that are encoded by two genes, TRalpha and TRbeta. Here, we provide direct evidence for the involvement of the TRalpha1 receptor isoform in vivo, by showing that the number of oligodendrocytes in the postnatal day 7 (P7) and P14 optic nerve of TRalpha1-/- mice is decreased compared with normal. We demonstrate that TRalpha1 mediates the normal differentiation-promoting effect of TH on oligodendrocyte precursor cells (OPCs): unlike wild-type OPCs, postnatal TRalpha1-/- OPCs fail to stop dividing and differentiate in response to TH in culture. We also show that overexpression of TRalpha1 accelerates oligodendrocyte differentiation in culture, suggesting that the level of TRalpha1 expression is normally limiting for TH-dependent OPC differentiation. Finally, we provide evidence that the inhibitory isoforms of TRalpha are unlikely to play a part in the timing of OPC differentiation. 相似文献
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Nuclear thyroid hormone (TH) receptors (TR) play a critical role in mediating the diverse actions of TH in development, differentiation, and metabolism of most tissues, but the role of TR isoforms in muscle development and function is unclear. Therefore, we have undertaken a comprehensive expression analysis of TRalpha 1, TRbeta 1, TRbeta 2 (TH binding), and TRalpha 2 (non-TH binding) in functionally distinct porcine muscles during prenatal and postnatal development. Use of a novel and highly sensitive RNase protection assay revealed striking muscle-specific developmental profiles of all four TR isoform mRNAs in cardiac, longissimus, soleus, rhomboideus, and diaphragm. Distribution of TR isoforms varied markedly between muscles; TRalpha expression was considerably greater than TRbeta and there were significant differences in the ratios TRalpha 1:TRalpha 2, and TRbeta 1:TRbeta 2. Together with immunohistochemistry of myosin heavy chain isoforms and data on myogenesis and maturation of the TH axis, these findings provide new evidence that highlights central roles for 1) TRalpha isoforms in fetal myogenesis, 2) the ratio TRalpha 1:TRalpha 2 in determining cardiac and skeletal muscle phenotype and function; 3) TRbeta in maintaining a basal level of cellular response to TH throughout development and a specific maturational function around birth. These findings suggest that events disrupting normal developmental profiles of TR isoforms may impair optimal function of cardiac and skeletal muscles. 相似文献
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Molecular conjugates of hormone receptor-ligands with molecular probes or functional domains are finding diverse applications in chemical biology. Whereas many examples of hormone conjugates that target steroid hormone receptors have been reported, practical ligand conjugates that target the nuclear thyroid hormone receptor (TRbeta) are lacking. TR-targeting conjugate scaffolds based on the ligands GC-1 and NH-2 and the natural ligand triiodothyronine (T3) were synthesized and evaluated in vitro and in cellular assays. Whereas the T3 or GC-1 based conjugates did not bind TRbeta with high affinity, the NH-2 inspired fluorescein-conjugate JZ01 showed low nanomolar affinity for TRbeta and could be used as a nonradiometric probe for ligand binding. A related analogue JZ07 was a potent TR antagonist that is 13-fold selective for TRbeta over TRalpha. JZ01 localizes in the nuclei of TRbeta expressing cells and may serve as a prototype for other TR-targeting conjugates. 相似文献
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O'Shea PJ Bassett JH Sriskantharajah S Ying H Cheng SY Williams GR 《Molecular endocrinology (Baltimore, Md.)》2005,19(12):3045-3059
Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status. 相似文献
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Weinhofer I Kunze M Rampler H Forss-Petter S Samarut J Plateroti M Berger J 《European journal of cell biology》2008,87(12):933-945
Adrenoleukodystrophy-related protein, a peroxisomal ABC transporter encoded by ABCD2, displays functional redundancy with the disease-associated X-linked adrenoleukodystrophy protein, making pharmacological induction of ABCD2 a potentially attractive therapeutic approach. Sterol regulatory element (SRE)-binding proteins (SREBPs) induce ABCD2 through an SRE overlapping with a direct repeat (DR-4) element. Here we show that thyroid hormone (T(3)) receptor (TR)alpha and TRbeta bind this motif thereby modulating SREBP1-dependent activation of ABCD2. Unliganded TRbeta, but not TRalpha, represses ABCD2 induction independently of DNA binding. However, activation by TRalpha and derepression of TRbeta are T(3)-dependent and require intact SRE/DR-4 motifs. Electrophoretic mobility shift assays with nuclear extracts support a direct interaction of TR and SREBP1 at the SRE/DR-4. In the liver, Abcd2 expression is high in young mice (with high T(3) and TRalpha levels) but downregulated in adults (with low T(3) and TRalpha but elevated TRbeta levels). This temporal repression of Abcd2 is blunted in TRbeta-deficient mice, and the response to manipulated T(3) states is abrogated in TRalpha-deficient mice. These findings show that TRalpha and TRbeta differentially modulate SREBP1-activated ABCD2 expression at overlapping SRE/DR-4 elements, suggesting a novel mode of cross-talk between TR and SREBP in gene regulation. 相似文献
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Gullberg H Rudling M Saltó C Forrest D Angelin B Vennström B 《Molecular endocrinology (Baltimore, Md.)》2002,16(8):1767-1777
T3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor beta (TRbeta), the most abundant TR isoform in rodent liver. Here, we have tested if TRalpha1, when expressed at increased levels from its normal locus, can replace TRbeta in regulation of cholesterol metabolism. By the use of TRalpha2-/-beta-/- animals that overexpress hepatic TRalpha1 6-fold, a near normalization of the total amount of T3 binding receptors was achieved. These mice are similar to TRbeta-/- and TRalpha1-/-beta-/- mice in that they fail to regulate cholesterol 7alpha-hydroxylase expression properly, and that their serum cholesterol levels are unaffected by T3. Thus, hepatic overexpression of TRalpha1 cannot substitute for absence of TRbeta, suggesting that the TRbeta gene has a unique role in T3 regulation of cholesterol metabolism in mice. However, examination of T3 regulation of hepatic target genes revealed that dependence on TRbeta is not general: T3 regulation of type I iodothyronine deiodinase and the low density lipoprotein receptor were partially rescued by TRalpha1 overexpression. These in vivo data show that TRbeta is necessary for the effects of T3 on cholesterol metabolism. That TRalpha1 only in some instances can substitute for TRbeta indicates that T3 regulation of physiological and molecular processes in the liver occurs in an isoform-specific fashion. 相似文献
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Suzuki H Zhang XY Forrest D Willingham MC Cheng SY 《Molecular endocrinology (Baltimore, Md.)》2003,17(5):895-907
Mutations in the thyroid hormone receptor (TR) beta gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRbeta mutation (TRbetaPV) with mice carrying a TRbeta null mutation (TRbeta(-/-)) to determine the consequences of the TRbetaPV mutation in the absence of wild-type TRbeta. TRbeta(PV/-) mice are distinct from TRbeta(+/-) mice that did not show abnormalities in thyroid function tests. TRbeta(PV/-) mice are also distinct from TRbeta(PV/+) and TRbeta(-/-) mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRbeta(PV/PV) mice. Similar to TRbeta(PV/PV) mice, TRbeta(PV/-) mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRbeta(PV/-) and TRbeta(PV/PV) mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRalpha1 for binding to thyroid hormone response elements in TRbeta(PV/-) mice as effectively as in TRbeta(PV/PV) mice. Thus, the actions of mutant TRbeta are markedly potentiated by the ablation of the second TRbeta allele, suggesting that interference with wild-type TRalpha1-mediated gene regulation by mutant TRbeta leads to severe RTH. 相似文献
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Esaki T Suzuki H Cook M Shimoji K Cheng SY Sokoloff L Nunez J 《American journal of physiology. Endocrinology and metabolism》2004,287(6):E1149-E1153
Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH beta-receptor (TRbeta) that eliminate its TH-binding ability lead to the thyroid hormone resistance syndrome (RTH) in humans, which is characterized by high blood TH levels, goiter, hyperactivity, and tachycardia. Mice with "knock-in" mutations in the TH alpha-receptor (TRalpha) or TRbeta that remove their TH-binding ability have been developed, and those with the mutated TRbeta (TRbeta(PV/PV)) appear to provide a model for RTH. These two types of mutants show different effects on cerebral energy metabolism, e.g., negligible change in glucose utilization (CMR(Glc)) in TRbeta(PV/PV) mice and markedly reduced CMR(Glc), like that found in cretinous rats, in the mice (TRalpha(PV/+)) with the knock-in mutation of the TRalpha gene. Studies in knockout mice have indicated that the TRalpha may also influence heart rate. Because mutations in both receptor genes appear to affect some parameters of cardiac function and because cardiac functional activity and energy metabolism are linked, we measured heart glucose utilization (HMR(Glc)) in both the TRbeta(PV/PV) and TRalpha(PV/+) mutants. Compared with values in normal wild-type mice, HMR(Glc) was reduced (-77 to -95%) in TRalpha(PV/+) mutants and increased (87 to 340%) in TRbeta(PV/PV) mutants, the degree depending on the region of the heart. Thus the TRalpha(PV/+) and TRbeta(PV/PV) mutations lead, respectively, to opposite effects on energy metabolism in the heart that are consistent with the bradycardia seen in hypothyroidism and the tachycardia associated with hyperthyroidism and RTH. 相似文献
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Cloning and characterization of two novel thyroid hormone receptor beta isoforms 总被引:1,自引:0,他引:1
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Williams GR 《Molecular and cellular biology》2000,20(22):8329-8342
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The timing of oligodendrocyte differentiation is thought to depend on both intracellular mechanisms and extracellular signals. Thyroid hormone (TH) helps control this timing both in vitro and in vivo, but it is still uncertain how it does so. TH acts through nuclear receptors that are encoded by two genes, TRalpha and TRbeta. Previous studies suggested that TRbeta receptors may mediate the effect of TH on oligodendrocyte precursor cells (OPCs). Consistent with this possibility, we show here that overexpression of TRbeta1 promotes precocious oligodendrocyte differentiation, whereas expression of two dominant-negative forms of TRbeta1 greatly delays differentiation. Surprisingly, however, we find that postnatal TRbeta-/- mice have a normal number of oligodendrocytes in their optic nerves and that TRbeta-/- OPCs stop dividing and differentiate normally in response to TH in vitro. Moreover, we find that OPCs do not express TRbeta1 or TRbeta2 mRNAs, whereas they do express TRalpha1 and TRalpha2 mRNAs. These findings suggest that alpha receptors mediate the effect of TH on the timing of oligodendrocyte differentiation. We also show that TRalpha2 mRNA, which encodes a dominant-negative form of TRalpha, decreases as OPCs proliferate in vitro and in vivo. This decrease may help control when oligodendrocyte precursors differentiate. 相似文献