Affinage

Showing THRA — TRALPHA is a alias.

THRA

Thyroid hormone receptor alpha · UniProt P10827

Length
490 aa
Mass
54.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THRA encodes thyroid hormone receptor alpha (TRα1, c-erbA alpha 1), a nuclear, ligand-dependent transcription factor that controls T3-responsive gene programs governing growth, differentiation, and metabolism (PMID:2537467, PMID:2903438, PMID:2554288, PMID:3054510, PMID:2903439). Its hormone-binding domain occupies the carboxy-terminal half of the protein, positionally analogous to that of steroid receptors (PMID:3359993, PMID:2464752), and TRα1 functions as a bona fide T3 receptor that restores hormone-responsive induction of endogenous genes (growth hormone, prolactin, malic enzyme, PEPCK, Na+/K+-ATPase) in receptor-deficient cells (PMID:2903439, PMID:2158623). A conserved 9-residue amphipathic helix at the extreme C-terminus (AF-2) is essential for T3-dependent transactivation, AP-1 interference, and erythroid differentiation, independently of T3 binding itself (PMID:8098843, PMID:1972036). TRα1 efficiently activates transcription only as part of an RXR heterodimer, with the unique C-terminus conferring heterodimerization competence on TREs (PMID:1318505), and unliganded receptor can repress competing pathways by sequestering RXR and dissociating RAR/RXR complexes (PMID:8096810); repression operates through corepressor and HDAC3 recruitment to chromatin (PMID:10921888). TRα1 acts as a ligand-controlled developmental switch: in the unliganded state it blocks NGF-induced neuronal differentiation, with T3 relieving the block (PMID:8385673). Receptor output is tuned at multiple layers from the same locus: alternative splicing produces TRα2, which cannot bind T3 and antagonizes TRα1/TRβ in dominant-negative fashion (PMID:2537467, PMID:2903438, PMID:2554288); an internal intron-7 promoter yields N-terminally truncated TRΔα isoforms that further attenuate TRα1 activity (PMID:9259319); the antisense Rev-ErbA alpha RNA shifts the α1/α2 ratio by inhibiting α2 splicing (PMID:1657988); and TRα1 is phosphorylated at N-terminal Ser12 by casein kinase II and at Ser28/29 by PKA/PKC (PMID:2903825, PMID:2552374). Germline truncating and missense THRA mutations cause resistance to thyroid hormone alpha (RTHα), a syndrome of low fT4/fT3 ratio, macrocephaly, and skeletal dysplasia, acting through reduced T3 binding and dominant-negative interference (PMID:25670821, PMID:26037512). Much of the early mechanistic dissection was performed through the constitutively repressive viral homolog v-ErbA, which lacks the AF-2 helix and functions as a dominant-negative oncogene antagonizing cellular TRα (PMID:2733791, PMID:1972036, PMID:1682217).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1988 High

    Before its function was defined, it was unknown whether the c-erbA alpha protein was itself a hormone receptor; locating the hormone-binding domain to the C-terminal half established it as a steroid/nuclear receptor-class molecule and pinpointed where ligand control resides.

    Evidence Chimeric v-erbA/c-erbA proteins and ligand-binding assays of in vitro translated deletion mutants

    PMID:2464752 PMID:3359993

    Open questions at the time
    • Structural basis of T3 binding not resolved
    • Did not address DNA target sequences or cofactor requirements
  2. 1988 High

    It was unclear whether c-erbA proteins were functional T3 receptors in cells; complementation in receptor-deficient lines showed they confer hormone-dependent regulation of growth hormone/prolactin and other endogenous genes, confirming receptor identity and predominantly nuclear localization.

    Evidence Transient expression with chimeric GH/PRL reporters in receptor-deficient versus receptor-containing cell lines; antibody fractionation and in vitro translation

    PMID:2903439 PMID:3054510

    Open questions at the time
    • Target gene repertoire incompletely mapped
    • Internal-initiation isoform functions not yet defined
  3. 1989 High

    The question of how a single locus produces opposing activities was answered by showing alternative splicing yields TRα1 (T3-activating) and TRα2 (non-T3-binding, dominant-negative), establishing intragenic antagonism as a regulatory principle.

    Evidence Transient transfection of T3-responsive reporters with in vitro translation and ligand-binding assays across multiple labs

    PMID:2537467 PMID:2554288 PMID:2903438

    Open questions at the time
    • Mechanism of TRα2 dominant-negativity not yet localized to a domain
    • Splicing control of the α1/α2 ratio unknown
  4. 1989 High

    To understand how the cellular receptor is post-translationally regulated, N-terminal phosphorylation sites were defined: PKA/PKC-enhanced Ser28/29 and casein kinase II-targeted Ser12, identifying kinase inputs onto receptor function.

    Evidence In vivo metabolic labeling, tryptic phosphopeptide mapping, in vitro kinase assays with purified PKA and CK2, and Ser12→Ala mutagenesis

    PMID:2552374 PMID:2903825

    Open questions at the time
    • Functional consequence of each phosphosite on transactivation not fully quantified
    • Upstream signals driving these modifications in vivo unknown
  5. 1989 High

    The transforming v-ErbA homolog was shown to be a constitutive repressor that dominantly blocks T3-dependent activation, providing the key tool to dissect activating versus repressive receptor functions; a zinc-finger DNA-binding mutation (Gly73→Ser) was linked to its loss of activation.

    Evidence Co-transfection of v-erbA/c-erbA with T3 reporters and chimeric ER/TRα DNA-binding-domain constructs

    PMID:1682217 PMID:1972036 PMID:1975094 PMID:2733791

    Open questions at the time
    • Repression mechanism (cofactors) not yet identified
    • Relative contributions of DNA-binding versus ligand-binding lesions unresolved
  6. 1990 High

    Mapping the difference between activating cellular receptor and repressive virus showed a conserved C-terminal 9-residue amphipathic helix (AF-2) is essential for T3-dependent transactivation, AP-1 interference, and erythroid differentiation, independent of T3 binding.

    Evidence c-ErbA/v-ErbA chimeras, single/double/triple substitution mutagenesis, reporter and erythroid differentiation assays

    PMID:1972036 PMID:8098843

    Open questions at the time
    • Identity of coactivators engaging AF-2 not defined
    • Structural mechanism of the helix not resolved
  7. 1991 High

    How TRα cross-talks with other signaling outputs was clarified by demonstrating ligand-activated TRα1 represses AP-1-driven collagenase transcription while v-ErbA fails to do so, linking receptor activity to control of cell growth.

    Evidence Co-transfection AP-1 reporter assays and retinoic-acid growth assays in chicken embryo fibroblasts

    PMID:1682056

    Open questions at the time
    • Molecular contact mediating AP-1 interference not mapped
    • Physiological relevance in mammals not tested here
  8. 1992 High

    The basis of differential isoform DNA binding was localized: the unique TRα1 C-terminus enables heterodimerization on TREs, whereas the unique TRα2 C-terminus is an inhibitory domain that reduces DNA binding.

    Evidence In vitro synthesis with EMSA and heterodimerization assays of TRα1, TRα2, deletion and chimeric mutants

    PMID:1318505

    Open questions at the time
    • Heterodimer partner identity not fully specified here
    • In vivo relevance of isoform DNA-binding differences untested
  9. 1993 High

    Mechanisms of trans-dominant antagonism were resolved: unliganded TRα suppresses RAR signaling by competing for shared RXR partner and dissociating RAR/RXR–RARE complexes, while v-ErbA functions chiefly through RXR heterodimerization and hinge-region-dependent trans-repression.

    Evidence EMSA dissociation and competition assays, RXR co-transfection rescue, and dimerization-interface/hinge mutagenesis (Pro349→Ser; Pro→Arg)

    PMID:7902566 PMID:8093812 PMID:8096810 PMID:8105369

    Open questions at the time
    • Quantitative contribution of competition versus active repression in vivo unclear
    • Endogenous gene targets of RXR sequestration not enumerated
  10. 1993 High

    TRα1 was established as a ligand-controlled developmental switch: unliganded receptor blocks NGF-induced neuronal differentiation and chromaffin commitment, with T3 relieving the neuronal block.

    Evidence Retroviral expression of TRα1/v-erbA in PC12 cells with NGF and dexamethasone differentiation and neuronal gene-expression assays; trk mRNA analysis in N2a cells

    PMID:8134111 PMID:8385673

    Open questions at the time
    • Direct target genes mediating the differentiation switch not all defined
    • In vivo developmental requirement not addressed in these systems
  11. 1996 Medium

    The corepressor logic underlying receptor-mediated silencing was advanced by showing the antisense locus product Rev-ErbA alpha binds N-CoR via two interaction domains, foreshadowing the corepressor machinery that TRα-class receptors deploy.

    Evidence Mammalian two-hybrid and co-transfection repression assays with dominant-negative N-CoR fragments

    PMID:8948627

    Open questions at the time
    • Direct demonstration on TRα1 itself not provided in this finding
    • Single-lab two-hybrid without structural validation
  12. 2000 High

    The chromatin-level repression mechanism was defined: v-ErbA recruits N-CoR and HDAC3 to repress, but unlike TRα requires mature chromatin and binds TFIIB poorly, dissecting why the viral protein silences less efficiently on partly assembled templates.

    Evidence Xenopus oocyte chromatin assembly assays, TSA treatment, Co-IP of N-CoR/HDAC3, and in vitro TFIIB binding

    PMID:10921888

    Open questions at the time
    • Equivalent stepwise mechanism for endogenous mammalian TRα not directly shown
    • Other corepressors/coactivators not surveyed
  13. 1997 Medium

    Additional layers of locus-encoded receptor tuning were identified: an internal intron-7 promoter generates N-terminally truncated TRΔα isoforms that selectively antagonize TRα1, and antisense Rev-ErbA alpha RNA inhibits TRα2 splicing to shift the α1/α2 ratio.

    Evidence 5′ RACE promoter identification with reporter co-transfection (TRΔα1) and in vitro splicing assays with strand-specific antisense RNA

    PMID:1657988 PMID:9259319

    Open questions at the time
    • Physiological abundance and tissue distribution of TRΔα isoforms not quantified
    • In vivo significance of antisense splicing regulation not established
  14. 2001 High

    Genetic epistasis in mice answered whether TRα1 and TRβ functions overlap, showing that increased TRα1 expression substitutes for loss of TRβ in deafness and thyroid hyperactivity, and that TRα2 is dispensable for hearing.

    Evidence Thra(tm2) allele in Thrb-null background with auditory brainstem response and thyroid hormone measurements

    PMID:11726557

    Open questions at the time
    • Tissues where TRα1 cannot substitute for TRβ not delineated here
    • Molecular basis of functional redundancy not addressed
  15. 2015 Medium

    The human disease relevance was established: germline THRA truncating and missense mutations cause resistance to thyroid hormone alpha (RTHα) through reduced T3 binding and dominant-negative interference, with genotype-phenotype correlation.

    Evidence Whole exome and Sanger sequencing in multiple families with longitudinal clinical/biochemical assessment, plus in vitro T3-binding, reporter, and dominant-negative assays of the N359Y mutant

    PMID:25670821 PMID:26037512

    Open questions at the time
    • Tissue-specific mechanisms of skeletal and growth phenotypes not fully resolved
    • Functional assays performed on limited mutation set

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers (splicing, antisense RNA, internal promoter, phosphorylation, cofactor recruitment) are integrated to set tissue-specific TRα1 output in human physiology and RTHα remains unresolved.
  • No integrated in vivo model linking phosphorylation, isoform ratios, and cofactor recruitment
  • Tissue-resolved target gene programs of TRα1 not comprehensively mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2 R-HSA-162582 Signal Transduction 1
Partners
HDAC3NCOR1RXRATFIIB

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 TRα1 (c-erbA alpha 1) functions as a ligand-dependent transcriptional activator of thyroid hormone-responsive genes, while the alternatively spliced variant TRα2 (c-erbA alpha 2) does not bind T3 but inhibits T3-dependent gene induction mediated by TRα1 or TRβ, establishing dominant-negative antagonism through alternative splicing of the same locus. Transient transfection of T3-responsive reporter genes in mammalian cells; in vitro translation and ligand-binding assays Nature High 2537467 2554288 2903438
1989 The v-erbA oncogene protein acts as a constitutive transcriptional repressor of thyroid hormone-responsive promoters and, when co-expressed with c-erbA/TRα, blocks T3-dependent transcriptional activation, establishing v-erbA as a dominant-negative oncogene that antagonizes its cellular homolog. Co-transfection of v-erbA and c-erbA expression vectors with T3-responsive reporter genes in cell lines; functional transcriptional assays Nature High 1682217 1972036 2733791
1988 The hormone-binding domain of c-erbA/TRα resides in the carboxy-terminal half of the protein; multiple mutations in this region of v-erbA cooperate to abolish T3 binding, and the ligand-binding domain is positionally analogous to that of steroid receptors. Chimeric v-erbA/c-erbA protein analysis; ligand-binding assays of in vitro translated deletion and chimeric mutants The EMBO journal High 2464752 3359993
1988 c-erbA/TRα protein (p46c-erbA) is phosphorylated on serine residues in its amino-terminal domain; one site (Ser28/Ser29) is shared with v-erbA and phosphorylation is enhanced 10-fold by activators of PKC or PKA; cAMP-dependent protein kinase directly phosphorylates both proteins in vitro at this site. In vivo metabolic labeling, tryptic phosphopeptide mapping, in vitro kinase assays with purified cAMP-dependent protein kinase The EMBO journal High 2903825
1989 c-erbA/TRα is phosphorylated at Ser12 in its amino-terminal domain by casein kinase II; the site contains an acidic context matching CK2 consensus; purified CK2 phosphorylates c-erbA at the same site in vitro; Ser12→Ala mutation abolishes CK2 phosphorylation in vitro. In vitro phosphorylation with purified casein kinase II; site-directed mutagenesis (Ser12→Ala); two-dimensional phosphopeptide mapping Oncogene High 2552374
1990 Phosphorylation of Ser-16/17 in the v-erbA-encoded domain of the gag/v-erbA fusion protein is required for its oncogenic function: Ser→Ala substitutions at these positions abolish phosphorylation, block inhibition of erythroid differentiation, and prevent suppression of erythrocyte-specific genes (band 3, CAII), while Ser→Thr substitution preserves basal but not PKA/PKC-enhanced phosphorylation and gives partial activity. Site-directed mutagenesis of Ser-16/17; retroviral expression in ts-v-erbB or ts-v-sea erythroblasts; in vivo and in vitro phosphorylation analysis; differentiation and gene expression assays Genes & development High 1979040
1990 A conserved 9-amino-acid sequence at the extreme C-terminus of c-ErbA alpha (deleted in v-ErbA) is essential for T3-dependent transcriptional activation, AP-1 transcriptional interference, and induction of erythroid differentiation; single, double, and triple amino acid substitutions within this region abolish both transactivation and AP-1 interference independently of their effect on T3 binding. c-ErbA/v-ErbA chimeras; site-directed mutagenesis; transient transfection reporter assays; erythroid differentiation assays Molecular and cellular biology High 8098843
1991 c-ErbA alpha (TRα1) represses AP-1-mediated transcriptional activation of the collagenase gene promoter by decreasing AP-1 activity in a ligand-activated manner; v-ErbA fails to repress AP-1 and acts as a dominant negative by overcoming c-ErbA alpha-mediated AP-1 repression, thereby abrogating growth-inhibitory responses to retinoic acid. Co-transfection of AP-1 reporter constructs with c-ErbA alpha or v-ErbA expression vectors; AP-1 activity assays; growth assays in chicken embryo fibroblasts with retinoic acid Cell High 1682056
1993 Unliganded TRα (c-ErbA alpha), but not v-ErbA, suppresses RAR-dependent transactivation by competing for the shared dimerization partner RXR; TRα/RXR competition dissociates preformed RAR/RXR–RARE ternary complexes in vitro; a single Pro349→Ser mutation in v-ErbA's dimerization interface abolishes this trans-dominant phenotype when introduced into TRα. Gel-shift (EMSA) showing dissociation of RAR/RXR–RARE complex; co-transfection with RXR to alleviate suppression; site-directed mutagenesis of dimerization interface The EMBO journal High 8096810
1993 v-ErbA requires heterodimerization with RXR-alpha for sufficient DNA binding to natural thyroid hormone response elements; only v-ErbA–RXR-alpha heterodimers bind TREs with the affinity required for potent transcriptional repression; C-terminal mutations that abolish v-ErbA–RXR-alpha heterodimerization also abolish repressor activity. EMSA heterodimerization assays; co-transfection with dominant-negative RXR; C-terminal mutagenesis of v-ErbA Oncogene High 8093812
1993 c-ErbA alpha (TRα1) activates transcription through an RSV-LTR T3 response element (RSV-T3RE) in the absence of ligand via a unique N-terminal activation domain; T3 reverses this ligand-independent activation; c-ErbA alpha/RXR heterodimers or c-ErbA alpha homodimers recognize this element; c-ErbA alpha adopts a different conformation on RSV-T3RE versus classical T3RE, enabling selective deployment of N-terminal vs. C-terminal activation domains. Transient transfection of RSV-T3RE reporter with c-ErbA alpha domain mutants; EMSA; N-terminal deletion analysis Cell High 7903219
1993 A 'hinge-region' Pro→Arg mutation in v-ErbA (equivalent to TRα hinge) selectively abolishes transcriptional repression (trans-repression) without affecting DNA binding or hormone binding of TRα, suggesting that trans-repression—not dominant-negative blockade of receptor activation—is the primary oncogenic function of v-erbA. Site-directed mutagenesis of hinge Pro→Arg in v-ErbA and TRα; co-transfection reporter assays; T3 and retinoic acid response assays Proceedings of the National Academy of Sciences of the United States of America High 7902566
1989 A DNA-binding mutation (Gly73→Ser) in the zinc-finger domain of v-ErbA is in part responsible for its inability to activate transcription; chimeric ER/TRα constructs with the v-erbA DNA-binding domain fail to activate reporters, whereas those with the c-erbA DNA-binding domain activate transcription. Chimeric estrogen/thyroid hormone receptor constructs; transient co-transfection reporter assays Nucleic acids research Medium 1975094
1991 v-ErbA and c-ErbA both bind directly to sequences within the CAII (carbonic anhydrase II) promoter; this erbA-binding site confers T3 responsiveness to a heterologous promoter; v-ErbA requires overexpression to overcome c-ErbA/T3-mediated activation at equimolar ratios in stably transformed erythroblasts. DNA-protein binding assays (EMSA/footprinting); stable retroviral co-expression of v-erbA and c-erbA; T3-responsive reporter and endogenous gene expression assays Genes & development High 1682217
1988 c-erbA/TRα1 protein and in vitro-translated c-erbA products are localized predominantly to the nucleus; multiple c-erbA-encoded proteins of 27–46 kDa arise from internal initiations within the c-erbA mRNA, generating a nested set of proteins; all are nuclear. Anti-erbA antibodies; immunoprecipitation; subcellular fractionation; in vitro translation; partial proteolytic mapping Molecular and cellular biology Medium 3054510
1988 c-erbA alpha and c-erbA beta proteins mediate thyroid hormone-dependent regulation of the rat growth hormone and prolactin gene regulatory sequences, functioning as T3 receptors; in receptor-deficient cells both act as hormone-dependent modulators, confirming their identity as functional T3 receptors. Transient expression of c-erbA alpha and c-erbA beta with chimeric GH/PRL reporter constructs in receptor-deficient (235-1) and receptor-containing (GH4C1, GH1) cell lines Molecular endocrinology (Baltimore, Md.) High 2903439
1990 The chicken c-erbA alpha protein restores T3 responsiveness (malic enzyme, PEPCK, Na+/K+-ATPase gene induction and direct activation of MLV promoter) in FAO receptor-deficient hepatoma cells in a ligand-dependent manner, proving it is a functional T3 receptor. Retroviral expression of cTR-alpha in FAO cells; Northern blot analysis of T3-responsive endogenous genes; T3 dose-response experiments Molecular endocrinology (Baltimore, Md.) High 2158623
1990 Overexpressed TRα (c-erbA/T3 receptor) modulates erythroid differentiation and erythrocyte-specific gene expression in a T3-dependent fashion in erythroid cells; v-erbA has lost the T3-dependent regulatory activity but constitutively displays a repressor function; the region responsible for loss of hormone-dependent activity in v-erbA maps to the extreme C-terminus of c-erbA, including a cluster of conserved residues forming a predicted amphipathic alpha-helix. Retroviral expression of chimeric v-/c-erbA proteins in erythroid cells; erythroid differentiation assays; erythrocyte gene expression analysis Cell High 1972036
1996 Rev-ErbA alpha (encoded on the opposite strand of the THRA locus) physically interacts with the corepressor N-CoR/RIP13 through a domain composed of two receptor interaction domains (ID-I and ID-II); this interaction requires an intact E (ligand-binding) region of Rev-ErbA alpha; overexpression of N-CoR interaction domains relieves Rev-ErbA alpha-mediated repression. Mammalian two-hybrid system; co-transfection repression assays with dominant-negative N-CoR fragments; deletion mutagenesis of Rev-ErbA alpha E region Nucleic acids research Medium 8948627
2000 v-ErbA recruits both N-CoR and HDAC3 to chromatin for transcriptional repression, but—unlike TRα—requires mature chromatin (not partial chromatinization) for this repression; v-ErbA is less competent than TRα for binding TFIIB in vitro and in vivo, explaining its impaired silencing on partly chromatinized templates. Xenopus oocyte chromatin assembly assays; histone deacetylase inhibitor (TSA) treatment; co-immunoprecipitation of N-CoR and HDAC3; in vitro TFIIB binding assays The EMBO journal High 10921888
1991 The antisense RNA Rev-ErbA alpha (transcribed from the opposite strand of the THRA locus) inhibits splicing of c-erbA alpha 2 pre-mRNA in vitro; both an antisense RNA spanning the 3′ splice site and a shorter exon-complementary RNA block splicing, suggesting that base-pairing with Rev-ErbA alpha shifts the alpha1/alpha2 ratio by inhibiting alpha2 mRNA splicing. In vitro splicing assay with c-erbA alpha 2 pre-mRNA; addition of antisense Rev-ErbA alpha RNA fragments; competition with non-complementary RNAs as control The Journal of biological chemistry High 1657988
1992 The unique C-terminus of TRα1 is required for heterodimerization with nuclear proteins on T3-response elements; the unique C-terminus of c-erbA alpha 2 acts as an inhibitory domain reducing DNA binding; chimera experiments show the last 100–150 aa of TRα1 are sufficient to confer heterodimerization competence on alpha 2. In vitro synthesis in E. coli and reticulocyte lysates; EMSA with TR alpha 1, alpha 2, and C-terminal deletion/chimeric mutants; heterodimerization assays on TREs Molecular endocrinology (Baltimore, Md.) High 1318505
1993 Unliganded TRα1 (c-erbA alpha) expressed in PC12 neuronal progenitor cells inhibits NGF-induced neuronal differentiation and represses neuron-specific gene expression; T3 binding relieves this inhibition, allowing normal differentiation; TRα1 also constitutively blocks dexamethasone-induced chromaffin differentiation, establishing TRα1 as a ligand-controlled switch for neuronal vs. chromaffin progenitor commitment. Retroviral expression of c-erbA/TR alpha-1 or v-erbA in PC12 cells; NGF and dexamethasone differentiation assays; neuronal gene expression analysis The Journal of cell biology High 8385673
1994 Unliganded TRα1 induces trkB mRNA expression (with concomitant loss of trkA and trkC) in N2a neuroblastoma cells in a ligand-independent manner; both TRα1 and TRβ1 produce this effect upon transient expression. Stable and transient expression of c-erbA/TR alpha 1 in N2a cells; Northern blot analysis of trk mRNAs; T3 treatment (no effect); tyrosine phosphorylation assay of induced gp145trkB Oncogene Medium 8134111
1997 Two novel N-terminally truncated isoforms of TRα (TRΔα1 and TRΔα2) are transcribed from an internal promoter within intron 7 of the c-erbA alpha gene; TRΔα1 antagonizes T3-dependent and retinoic-acid-dependent transcriptional activation by TRα1 and 9-cis-RAR alpha but does not affect RAR alpha-dependent activation. Identification of internal promoter by 5′ RACE; expression vector transfection; T3- and RA-responsive reporter assays with TRΔα1 co-expression Molecular endocrinology (Baltimore, Md.) Medium 9259319
2001 A targeted mutation in Thra (Thra(tm2)) that deletes TRα2 and causes overexpression of TRα1 suppresses the deafness and thyroid hyperactivity phenotypes of Thrb-null mice, indicating that increased TRα1 expression can substitute for loss of TRβ and that TRα2 is dispensable for hearing. Genetic epistasis: Thra(tm2) allele introduced into Thrb(tm1/tm1) null background; auditory brainstem response thresholds; thyroid hormone measurements Human molecular genetics High 11726557
2015 Truncating and missense mutations in THRA cause a distinct resistance-to-thyroid-hormone syndrome (RTHα) with low fT4/fT3 ratio, macrocephaly, and skeletal dysplasia; missense mutations show milder phenotypes than truncating mutations (genotype-phenotype correlation), establishing THRA as the causal gene. Whole exome sequencing followed by Sanger sequencing; longitudinal clinical assessment; biochemical thyroid function tests in six patients from five families Journal of medical genetics Medium 25670821
2015 A de novo missense mutation in THRA (N359Y) affecting TRα1 causes decreased T3 binding affinity and a dominant-negative effect on wild-type TRα1-mediated transcription; the mutation also affects the non-receptor isoform TRα2. Whole exome sequencing; in vitro transcriptional activity assays of mutant vs. wild-type TRα1; T3 binding assays; dominant-negative co-transfection assays The Journal of clinical endocrinology and metabolism Medium 26037512
1988 v-ErbA protein exists in both nuclear and cytoplasmic forms; both forms can bind DNA; a mutation that inhibits DNA binding also inhibits nuclear localization and abolishes the ability to potentiate erythroid transformation, linking DNA binding to nuclear localization and oncogenic function. Site-specific antisera; subcellular fractionation; DNA binding assays; biological transformation assays Journal of virology Medium 2826814
1990 A subpopulation of the v-erbA protein (a TRα-derived nuclear receptor) is glycosylated, identifying TRα-related proteins as members of the glycoprotein class of nuclear transcription factors. Metabolic labeling with [3H]-glucosamine; glycosidase treatment; immunoprecipitation Journal of virology Low 1967151
1993 ErbA oncogene protein (v-ErbA) interferes with TRα and trans-retinoic acid receptors by competing for binding to their respective DNA response elements; v-ErbA does not heterodimerize with RAR or TR in a functionally significant manner for repression of these receptors, but efficiently heterodimerizes with RXR, which dramatically impairs RXR-mediated gene activation. EMSA competition assays; co-transfection reporter assays; heterodimerization assays Molecular and cellular biology Medium 8105369

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1986 The chicken oestrogen receptor sequence: homology with v-erbA and the human oestrogen and glucocorticoid receptors. The EMBO journal 645 3755102
1989 Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature 616 2733791
1989 Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature 433 2537467
1987 Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Molecular and cellular biology 369 3299059
1988 Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. Proceedings of the National Academy of Sciences of the United States of America 312 2901090
1989 A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. Molecular and cellular biology 309 2542765
1983 Transforming capacities of avian erythroblastosis virus mutants deleted in the erbA or erbB oncogenes. Cell 301 6297784
1988 Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene 284 3281095
1990 Relationship of c-erbA mRNA content to tissue triiodothyronine nuclear binding capacity and function in developing and adult rats. The Journal of biological chemistry 283 2162351
1988 Identification of a rat c-erbA alpha-related protein which binds deoxyribonucleic acid but does not bind thyroid hormone. Molecular endocrinology (Baltimore, Md.) 275 2903438
1990 Differential and tissue-specific regulation of the multiple rat c-erbA messenger RNA species by thyroid hormone. The Journal of clinical investigation 250 2153150
1989 Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 244 2539258
1990 v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA. Cell 240 1972036
1993 The orphan receptor Rev-ErbA alpha activates transcription via a novel response element. Molecular and cellular biology 208 8474464
1984 Chromosomal localisation of the human homologues to the oncogenes erbA and B. The EMBO journal 199 6323162
1991 Independent expression of the alpha and beta c-erbA genes in developing rat brain. Molecular endocrinology (Baltimore, Md.) 194 1663215
1990 A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. The Journal of clinical investigation 178 2153155
1993 Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. The Journal of biological chemistry 172 8344913
1988 Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene. Molecular endocrinology (Baltimore, Md.) 161 2905763
1991 A novel mechanism of action for v-ErbA: abrogation of the inactivation of transcription factor AP-1 by retinoic acid and thyroid hormone receptors. Cell 159 1682056
1986 v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation. Cell 159 3009024
1988 v-erbA specifically suppresses transcription of the avian erythrocyte anion transporter (band 3) gene. Cell 157 2830979
1988 Activation of protein kinase C or cAMP-dependent protein kinase increases phosphorylation of the c-erbA-encoded thyroid hormone receptor and of the v-erbA-encoded protein. The EMBO journal 155 2903825
1991 Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA. The Journal of biological chemistry 149 1657988
1988 c-erbA protooncogenes mediate thyroid hormone-dependent and independent regulation of the rat growth hormone and prolactin genes. Molecular endocrinology (Baltimore, Md.) 147 2903439
1984 A human c-erbA oncogene homologue is closely proximal to the chromosome 17 breakpoint in acute promyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 141 6589608
1989 Human carboxyl-terminal variant of alpha-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone. Proceedings of the National Academy of Sciences of the United States of America 134 2554288
1997 Identification of transcripts initiated from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities. Molecular endocrinology (Baltimore, Md.) 132 9259319
1988 Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein. The EMBO journal 127 3359993
1989 Presence of two members of c-erbA receptor gene family (c-erbA beta and c-erbA2) in smallest region of somatic homozygosity on chromosome 3p21-p25 in human breast carcinoma. Journal of the National Cancer Institute 126 2573734
1991 A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Molecular endocrinology (Baltimore, Md.) 121 1653889
1993 A novel cis element mediating ligand-independent activation by c-ErbA: implications for hormonal regulation. Cell 120 7903219
1987 Expression of the v-erbA oncogene in chicken embryo fibroblasts stimulates their proliferation in vitro and enhances tumor growth in vivo. Cell 113 2884040
1991 Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene. Nucleic acids research 106 1850510
1984 Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene. Science (New York, N.Y.) 103 6328658
1993 A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor). Molecular and cellular biology 102 8098843
2002 Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene 98 12082618
1989 Expression of the v-erbA product, an altered nuclear hormone receptor, is sufficient to transform erythrocytic cells in vitro. Cell 98 2568887
2000 Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(alpha) orphan receptor. Development (Cambridge, England) 97 10704394
1993 Unliganded T3R, but not its oncogenic variant, v-erbA, suppresses RAR-dependent transactivation by titrating out RXR. The EMBO journal 92 8096810
1987 A single point mutation in erbA restores the erythroid transforming potential of a mutant avian erythroblastosis virus (AEV) defective in both erbA and erbB oncogenes. The EMBO journal 92 2884103
1991 v-erbA overexpression is required to extinguish c-erbA function in erythroid cell differentiation and regulation of the erbA target gene CAII. Genes & development 89 1682217
1990 Phosphorylation of the v-erbA protein is required for its function as an oncogene. Genes & development 89 1979040
1990 The viral erbA oncogene protein, a constitutive repressor in animal cells, is a hormone-regulated activator in yeast. Cell 87 1979758
1989 The c-erbA alpha-encoded thyroid hormone receptor is phosphorylated in its amino terminal domain by casein kinase II. Oncogene 86 2552374
1980 Nucleotide sequence of the thrA gene of Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 86 7003595
1995 Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family. Molecular endocrinology (Baltimore, Md.) 85 8614403
1989 c-erbB-2/c-erbA co-amplification indicative of lymph node metastasis, and c-myc amplification of high tumour grade, in human breast carcinoma. British journal of cancer 81 2572268
1996 Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors. Nucleic acids research 79 8948627
1994 Thyroid abnormalities and hepatocellular carcinoma in mice transgenic for v-erbA. The EMBO journal 76 7925269
1993 v-erbA and citral reduce the teratogenic effects of all-trans retinoic acid and retinol, respectively, in Xenopus embryogenesis. Development (Cambridge, England) 76 7910550
1993 Thyroid hormone receptor/c-erbA: control of commitment and differentiation in the neuronal/chromaffin progenitor line PC12. The Journal of cell biology 76 8385673
1990 Characterization of site-specific polyclonal antibodies to c-erbA peptides recognizing human thyroid hormone receptors alpha 1, alpha 2, and beta and native 3,5,3'-triiodothyronine receptor, and study of tissue distribution of the antigen. Endocrinology 72 1693571
1988 Regulation of two c-erbA messenger ribonucleic acids in rat GH3 cells by thyroid hormone. Molecular endocrinology (Baltimore, Md.) 72 2901667
2015 Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA). Journal of medical genetics 70 25670821
1988 c-erbA encodes multiple proteins in chicken erythroid cells. Molecular and cellular biology 68 3054510
1991 A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance. The Journal of clinical endocrinology and metabolism 67 1846005
1993 An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype. The Journal of clinical investigation 66 8381821
1988 erbA-related sequence coding for DNA-binding hormone receptor localized to chromosome 3p21-3p25 and deleted in small cell lung carcinoma. Cancer research 62 2891438
1994 c-erbA alpha/T3R and RARs control commitment of hematopoietic self-renewing progenitor cells to apoptosis or differentiation and are antagonized by the v-erbA oncogene. Oncogene 61 7906409
1993 Identification of a domain required for oncogenic activity and transcriptional suppression by v-erbA and thyroid-hormone receptor alpha. Proceedings of the National Academy of Sciences of the United States of America 60 7902566
1991 Thyroid hormone receptor/and v-erbA. A single amino acid difference in the C-terminal region influences dominant negative activity and receptor dimer formation. The Journal of biological chemistry 60 1675637
2000 Targeting of N-CoR and histone deacetylase 3 by the oncoprotein v-erbA yields a chromatin infrastructure-dependent transcriptional repression pathway. The EMBO journal 59 10921888
1989 Characterization of the domain structure of chick c-erbA by deletion mutation: in vitro translation and cell transfection studies. Molecular endocrinology (Baltimore, Md.) 57 2464752
1993 The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms. Molecular and cellular biology 56 8105369
2000 Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. Molecular endocrinology (Baltimore, Md.) 55 10809233
1991 Regulation of c-erbA-alpha messenger RNA species in tadpole erythrocytes by thyroid hormone. Molecular endocrinology (Baltimore, Md.) 54 1645454
1992 The v-erbA oncogene requires cooperation with tyrosine kinases to arrest erythroid differentiation induced by ligand-activated endogenous c-erbA and retinoic acid receptor. Oncogene 53 1347913
1991 The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis. Molecular and cellular biology 51 1656222
1989 Expression of the ErbA-beta class of thyroid hormone receptors is selectively lost in human colon carcinoma. The Journal of clinical investigation 50 2553781
2015 A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. The Journal of clinical endocrinology and metabolism 47 26037512
1993 V-erbA requires auxiliary proteins for dominant negative activity. Oncogene 47 8093812
1988 The avian erythroblastosis virus erbA oncogene encodes a DNA-binding protein exhibiting distinct nuclear and cytoplasmic subcellular localizations. Journal of virology 47 2826814
1992 The unique C-termini of the thyroid hormone receptor variant, c-erbA alpha 2, and thyroid hormone receptor alpha 1 mediate different DNA-binding and heterodimerization properties. Molecular endocrinology (Baltimore, Md.) 44 1318505
1990 The lack of transcriptional activation of the v-erbA oncogene is in part due to a mutation present in the DNA binding domain of the protein. Nucleic acids research 44 1975094
1991 Ontogeny of the v-erbA oncoprotein from the thyroid hormone receptor: an alteration in the DNA binding domain plays a role crucial for v-erbA function. Journal of virology 42 1672166
1990 Isolation of a cDNA encoding human Rev-ErbA alpha: transcription from the noncoding DNA strand of a thyroid hormone receptor gene results in a related protein that does not bind thyroid hormone. DNA and cell biology 41 1971514
2001 Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene. Human molecular genetics 40 11726557
1990 Expression of erbA alpha and beta mRNAs in regions of adult rat brain. Molecular and cellular endocrinology 40 2160381
1987 Nucleotide sequence of the chicken proto-oncogene c-erbA corresponding to domain 1 of v-erbA. European journal of biochemistry 40 3036525
1998 Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. Molecular endocrinology (Baltimore, Md.) 39 9482666
1994 Roles of v-erbA homodimers and heterodimers in mediating dominant negative activity by v-erbA. The Journal of biological chemistry 38 7904604
1988 Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene. Molecular and cellular biology 38 2847034
1999 Hepatocyte nuclear factor 4-mediated activation of rat CYP3A1 gene and its modes of modulation by apolipoprotein AI regulatory protein I and v-ErbA-related protein 3. Archives of biochemistry and biophysics 37 9917326
1990 Thyroid hormone and DNA binding properties of a mutant c-erbA beta receptor associated with generalized thyroid hormone resistance. Biochemical and biophysical research communications 37 2169728
2019 Bisphenol A Alters Bmal1, Per2, and Rev-Erba mRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons. Endocrinology 35 30500912
1999 The v-erbA oncogene (review). International journal of molecular medicine 35 10493974
1990 Sequence-specific DNA binding by the v-erbA oncogene protein of avian erythroblastosis virus. Journal of virology 33 1968105
1994 Unliganded c-erbA/thyroid hormone receptor induces trkB expression in neuroblastoma cells. Oncogene 31 8134111
1992 An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity. The Journal of clinical endocrinology and metabolism 31 1314846
1992 V-erbA and c-erbA proteins enhance transcriptional activation by c-jun. Oncogene 31 1349165
1990 The carbonic anhydrase II gene, a gene regulated by thyroid hormone and erythropoietin, is repressed by the v-erbA oncogene in erythrocytic cells. The New biologist 30 2126201
1988 Antipeptide antibodies recognize c-erbA and a related protein in human A431 carcinoma cells. Endocrinology 30 2904357
1995 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. Molecular and cellular endocrinology 29 7796935
1990 Requirement for the C-terminal domain of the v-erbA oncogene protein for biological function and transcriptional repression. Oncogene 29 1969136
1990 A subpopulation of the avian erythroblastosis virus v-erbA protein, a member of the nuclear hormone receptor family, is glycosylated. Journal of virology 28 1967151
1997 Deoxyribonucleic acid binding and transcriptional silencing by a truncated c-erbA beta 1 thyroid hormone receptor identified in a severely retarded patient with resistance to thyroid hormone. The Journal of clinical endocrinology and metabolism 26 9100577
1997 Mechanism of transformation by v-ErbA: substitution for steroid hormone receptor function in self renewal induction. Oncogene 25 9264411
1993 v-erbA acts on retinoic acid receptors in immature avian erythroid cells. Journal of virology 24 8093487
1990 The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells. Molecular endocrinology (Baltimore, Md.) 24 2158623

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