focused on elucidating the anti-diabetic mechanism of PPARγ, especially the development of ligands and the discovery of modulators that regulate PPARγ functions. Thyroid hormone receptor-associated protein 3 (THRAP3), also called TRAP150, is a
Juu-Chin Lu, Chia-Yun Lu, and Ying-Yu Wu
Xin Liu, Nan Zheng, Ya-Nan Shi, Jihong Yuan, and Lanying Li
). Bergh et al . (2005) identified integrin αvβ3 as a cell surface receptor for thyroid hormone (T 4 ) and as the initiation site for T 4 -induced angiogenesis. The extracellular domain of integrin αvβ3 includes an Arg-Gly-Asp (RGD) recognition site that
Limin Tian, Luyan Zhang, Jing Liu, Tiankang Guo, Cuixia Gao, and Jing Ni
receptor (TSHR) is expressed on thyroid cells and plays a central role in upregulating the function of the thyroid, including the synthesis of TH. Increasing evidence indicates that TSHR is also expressed by many nonthyroid tissues and cells, such as
Gabriela Placoná Diniz, Ana Paula Cremasco Takano, Erika Bruneto, Francemilson Goulart da Silva, Maria Tereza Nunes, and Maria Luiza Morais Barreto-Chaves
of rat and improves glucose homeostasis . Thyroid 22 70 – 79 . doi:10.1089/thy.2010.0409 . Cao HJ Lin HY Luidens MK Davis FB Davis PJ 2009 Cytoplasm-to-nucleus shuttling of thyroid hormone receptor-β1 (Trβ1) is directed from a
The nuclear receptor family responds to a diverse group of ligands, including steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. Previous sequence analyses of adrenal and sex steroid receptors indicate that they form a clade separate from other nuclear receptors. However, the relationships of adrenal and sex steroid receptors to each other and to their ancestors are not fully understood. We have used new information from androgen, estrogen, mineralocorticoid and progesterone receptors in fish to better resolve the phylogeny of adrenal and sex steroid receptors. Sequence divergence between fish and mammalian steroid receptors correlates with differences in steroid specificity, suggesting that phylogeny needs to be considered in evaluating the endocrine effects of xenobiotics. Among the vertebrate steroid receptors, the most ancient is the estrogen receptor. The phylogeny indicates that adrenal and sex steroid receptors arose in a jawless fish or a protochordate and that changes in the sequence of the hormone-binding domain have slowed considerably in land vertebrates. The retinoid X receptor clade is closest to the adrenal and sex steroid receptor clade. Retinoid X receptor is noteworthy for its ability to form dimers with other nuclear receptors, an important mechanism for regulating the action of retinoid X receptor and its dimerization partners. In contrast, the adrenal and sex steroid receptors bind to DNA as homodimers. Moreover, unliganded adrenal and sex steroid receptors form complexes with heat shock protein 90. Thus, the evolution of adrenal and sex steroid receptors involved changes in protein-protein interactions as well as ligand recognition.
Ana Luiza R Rolim, Susan C Lindsey, Ilda S Kunii, Felipe Crispim, Regina Célia M S Moisés, Rui M B Maciel, and Magnus R Dias-da-Silva
Introduction Thyrotoxic periodic paralysis (TPP) is an acute manifestation of thyrotoxicosis and is characterised by transient episodes of flaccid muscle paralysis, hypokalaemia and hypophosphataemia that occur only in the presence of high thyroid
SM Huang, CJ Huang, WM Wang, JC Kang, and WC Hsu
The p160 coactivators, steroid receptor coactivator 1, glucocorticoid receptor interacting protein 1 (GRIP1) and the activator of thyroid and retinoic acid receptor, have two activation domains, AD1 and AD2, which transmit the activation signal from the DNA-bound nuclear receptor to the chromatin and/or transcription machinery. In screening for mammalian proteins that bind the AD2 of GRIP1, we identified a mouse actin-binding protein, alpha actinin 2 (mACTN2). mACTN2 was expressed in the heart, skeletal muscle, lung, brain and testis, but there was no expression in the spleen, liver or kidney. Interestingly, the expression level of mACTN2 in the developing embryo depended on the embryonic stage. We further demonstrated that mACTN2 could enhance two transactivation activities of GRIP1, which in turn could enhance the homodimerization of mACTN2. Importantly, mACTN2 not only served as a primary coactivator for androgen receptor, estrogen receptor and thyroid receptor activities, but also acted synergistically with GRIP1 to enhance these nuclear receptor (NR) functions. However, the NR binding motif, LXXLL, conserved in mACTN2 and other actinin family proteins, might be a dispensable domain for its coactivator roles in NRs. These findings suggested that mACTN2 might play an important role in GRIP1-induced NR coactivator functions.
S. Palmero, M. Benahmed, A. M. Morera, P. Trucchi, and E. Fugassa
The existence of nuclear tri-iodothyronine (T3) receptors in both Sertoli and Leydig cells isolated from immature piglet testes was investigated. The results demonstrated the presence of high-affinity (K d=1·09±0·25 nm), low-capacity (185±24pg T3/mg DNA) binding sites for T3 in nuclei from freshly isolated Sertoli cells. No specific binding for T3 was observed in nuclei isolated from Leydig cells. The localization of specific T3 receptors, which might mediate the onset of thyroid hormone action, at Sertoli cell level confirms that these cells are a target for thyroid hormone and strongly sustain the role of the thyroid in the regulation of testicular functions during postnatal development.
K. Ichikawa, K. Hashizume, Y. Nishii, T. Takeda, M. Kobayashi, S. Suzuki, and T. Yamada
Human thyroid hormone receptor (c-erb A protein) produced by Escherichia coli expression vector plasmid was purified sequentially using polyethylenimine precipitation of DNA, hydroxylapatite column chromatography, ammonium sulphate precipitation, Sephacryl S-300 gel filtration and mono Q-Sepharose column chromatography. These column procedures resulted in 41.3-fold purification of 3,5,3′-tri-iodo-l-thyronine (T3) binding activity over the initial E. coli extract. Purified protein as well as crude preparation showed high-affinity binding to T3. The c-erb A protein enriched by column purification was further purified by electroelution after electrophoresis. Rabbit antibody against the c-erb A protein was prepared and used for the Western blotting analysis. The antibody recognized c-erb A protein but not the bacterial proteins in crude E. coli extract. When partially purified rat hepatic nuclear thyroid hormone receptor was analysed, a 56kDa receptor was specifically recognized by the antibody.
From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.