Disease relevance of THRA

• In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively [1].
• In human acute promyelocytic leukemia (APL) and avian erythroleukemia (AEL), chromosomal translocations and/or mutations in nuclear hormone receptors, RARalpha [NR1B1] and TRalpha [NR1A1], yielded oncoproteins that deregulate transcription and alter chromatin structure [2].
• In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease [3].
• Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA beta receptor [4].
• Unlike classical HREs, this element, RSV-T3RE (found in Rous sarcoma virus-long terminal repeat), mediates strong activation by the c-ErbA alpha thyroid hormone (T3) receptor in the absence of T3, and addition of T3 reverses this response [5].

High impact information on THRA

• We report here that v-erbA can actually interfere with the actions of a variety of members of the steroid/retinoid receptor family and that the ability of v-erbA to act in neoplasia best correlates not with suppression of c-erbA action, but with interference with the retinoic acid receptor response [6].
• Here we show that the overexpressed thyroid hormone receptor c-erbA effectively modulates erythroid differentiation and erythrocyte-specific gene expression in a T3-dependent fashion, when introduced into erythroid cells via a retrovirus [7].
• v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA [7].
• Alternative splicing of the erbA alpha transcript thus generates products with opposing biological activities, suggesting a novel mechanism for the modulation of hormonal responsiveness [8].
• Proteins encoded by two cellular proto-oncogenes, c-erbA alpha and beta, bind T3 and can act as functional T3 receptors [8].

Chemical compound and disease context of THRA

• PATIENTS AND METHODS: The French Society of Pediatric Oncology initiated its first cooperative Ewing's sarcoma study in 1978, using a four-drug regimen (cyclophosphamide, dactinomycin, Adriamycin [doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France], and vincristine) [9].
• In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM) [10].
• Attempting to develop a new active, convenient regimen, we initiated a phase I study of paclitaxel (Taxol; Bristol-Myers squibb Company, Princeton, NJ) combined with epirubicin (Farmitalia Carlo Erba, Milan, Italy) in patients with metastatic breast cancer [11].
• Different weekly doses (400 to 3,000 micrograms) of the new, long-acting dopamine agonist Cabergoline (Farmitalia Carlo Erba, Milan, Italy) were given to 11 hyperprolactinemic women with pituitary tumor [12].
• Triclosan alone altered thyroid hormone receptor alpha transcript levels in the brain of premetamorphic tadpoles and induced a transient weight loss [13].

Biological context of THRA

• The rat erbA alpha locus encodes two overlapping mRNAs, alpha 1 and alpha 2, which are identical except for their most 3' exons. alpha 1 mRNA encodes a thyroid hormone receptor, while alpha 2 encodes an altered ligand binding domain of unknown function [14].
• Chromosomal assignment of five cancer-associated rat genes: two thyroid hormone receptor (ERBA) genes, two ERBB genes and the retinoblastoma gene [15].
• Recent data suggest an interaction between the DNA-binding domains of mammalian MEF2 proteins and those of tissue-specific basic helix-loop-helix (bHLH) factors and thyroid hormone receptor alpha 1 (TR alpha 1) in the expression of target genes and the development of specific cell phenotypes [16].
• This cDNA contains 269 consecutive base pairs identical to a region of a human c-erbA alpha-2 cDNA, but the respective long open reading frames utilize this nucleotide sequence in opposite orientations [17].
• The conservation of the bidirectionally transcribed regions of c-erbA alpha-2 and Rev-ErbA alpha in human and rat suggests that this unusual genomic arrangement has an important function, perhaps related to the regulation of gene expression [17].

Anatomical context of THRA

• The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes that encode nuclear receptors for various hydrophobic ligands such as steroids, retinoic acid and thyroid hormones [18].
• Here we show that human thyroid hormone receptor alpha purified from HeLa cells grown in the presence of thyroid hormone (T3) is associated with a group of distinct nuclear proteins termed thyroid hormone receptor-associated proteins (TRAPs) [19].
• Likewise, enhanced expression of exogenous c-erbA/TR-alpha in erythroblasts rendered them susceptible to modulation of differentiation by T3, suggesting a similar function of both receptors [20].
• Here we show that the ligand-activated, endogenous retinoic acid receptor (RAR-alpha), in cooperation with c-erbA/TR-alpha, efficiently reverses the transforming effect of kinase oncogenes, overcoming oncogene-induced self-renewal by triggering terminal differentiation of the transformed cells into healthy erythrocytes [21].
• A cDNA that encodes a third type of human thyroid hormone receptor (hTR alpha 1) has been isolated from a skeletal muscle library [22].

Associations of THRA with chemical compounds

• 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 [23].
• The c-erbA gene belongs to a multigene family that encodes transcriptional regulatory proteins including the v-erbA oncogene product, steroid hormone receptors, and the vitamin D3 receptor [24].
• The v-erbA oncogene, a mutated version of the thyroid hormone receptor alpha (c-erbA/TR-alpha), cooperates with tyrosine kinase oncogenes in erythroblast transformation [21].
• TR alpha 1 formed a heterodimer with 9-cis retinoic acid receptor alpha (RXR alpha) on all TREs studied [25].
• The variant consisting of a cytosine to adenine base substitution at nucleotide position 1650 altered phenylalanine to leucine in codon 450 in the T3-binding domain of c-erbA beta [26].

Physical interactions of THRA

• Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene [27].
• Here, we show that v-erbA and c-erbA bind directly to sequences within the promoter of the erythrocyte-specific carbonic anhydrase II (CAII), a gene whose transcription is efficiently suppressed by v-erbA [28].

Enzymatic interactions of THRA

• Purified casein kinase II as well as a reticulocyte casein kinase II-like activity phosphorylated TR alpha 2 on serines 474 and 475 [29].

Regulatory relationships of THRA

• The v-erbA oncogene requires cooperation with tyrosine kinases to arrest erythroid differentiation induced by ligand-activated endogenous c-erbA and retinoic acid receptor [21].
• A shift in the ligand responsiveness of thyroid hormone receptor alpha induced by heterodimerization with retinoid X receptor alpha [30].
• These results indicate that hTR beta 1 expression is directly regulated by hTR alpha 1, beta 1, and their ligand through two TREs [31].
• These findings suggest that cell-specific factors control the ability of TR alpha to regulate the malic enzyme gene [32].

Other interactions of THRA

• In addition, TRAP may interact with a certain subset of the nuclear receptor superfamily, since human retinoic acid receptor-beta and vitamin D receptor show increased binding to TREs in the presence of nuclear extract, but c-erbA alpha-2, a variant TR, does not respond to TRAP [33].
• The phenotypic manifestations of mutated THRB and THRA genes are distinct, indicating isoform-dependent actions of TR mutants in vivo [34].
• We then used carboxyl-terminal truncations of rat TR alpha-1 and human TR beta in the avidin-biotin complex DNA-binding assay to identify regions that are important for interaction with TRAP [33].
• Two clinical variants, generalized resistance to thyroid hormone (GRTH) and selective pituitary resistance to thyroid hormone (PRTH), are, in most cases, caused by heterozygous mutations in the ligand-binding domain of the c-erbA beta thyroid hormone receptor gene [35].
• Four thyroid nuclear receptors have been described in tissues, TR alpha 1, alpha 2, beta 1, and beta 2 [36].

Analytical, diagnostic and therapeutic context of THRA

• Gel mobility shift assays showed both proximal and distal TREs formed a retarded band with hTR alpha 1 or hTR beta 1 expressed in COS1 cells and reticulocyte lysates [31].
• To accomplish this, the missing 5'-sequence of a previously isolated partial RC c-erbA alpha cDNA (RC12) was synthesized by polymerase chain reaction (PCR) and spliced to RC12 to yield a 1490-basepair cDNA (RC15) that contained the entire coding sequence of the receptor protein [37].
• There were no differences in the histologic type, cellular atypism, mitotic index, and other disease parameters between tumors with c-erbB-2 amplification only and those with coamplification of c-erbB-2 and c-erbA-1 [38].
• All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2) [39].
• Despite abundant TR protein expression, Northern blot hybridization of polyadenylated ribonucleic acid (RNA; 10 micrograms) to TR complementary DNAs revealed only a weak signal for c-erbA alpha 2 messenger RNA (mRNA) [40].

References