RGD Reference Report - Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes. - Rat Genome Database

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Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes.

Authors: Katz, D  Lazar, MA 
Citation: Katz D and Lazar MA, J Biol Chem. 1993 Oct 5;268(28):20904-10.
RGD ID: 1580108
Pubmed: PMID:8407924   (View Abstract at PubMed)

Regulation of development and metabolism by thyroid hormone (T3) may be influenced by a non-T3 binding T3 receptor (TR) isoform, TR alpha 2, which can inhibit transcriptional activation by legitimate TRs. Numerous mechanisms have been postulated to explain the dominant negative actions of TR alpha 2, including competition for target genes, formation of inactive heterodimers, and squelching. We have found that excess TR alpha 2 was required to inhibit TR alpha 1-mediated transactivation from multiple T3 response elements (TREs). Inhibition of T3 action by TR alpha 2 was specific for TRE-containing genes, because a GAL4/TR alpha 1 chimera, which heterodimerized with the 9-cis-retinoic acid receptor (RXR) and activated transcription from the GAL4 binding site in the presence of T3, was not inhibited by TR alpha 2. In contrast, TR alpha 2 inhibited transactivation by TR alpha/VP16, a chimeric protein containing the N-terminal DNA binding domain (DBD) of TR alpha 1 fused to the transcriptional activation domain of VP16. Indeed, TR alpha 2 inhibited the binding of TR alpha 1 monomers, homodimers, and RXR-heterodimers to DNA in vitro, whereas the TR alpha 2 C terminus alone did not. Although TR alpha 2 bound to TREs with less affinity than TR alpha 1, it bound directly to target genes in the cell nucleus. Furthermore, a TR alpha 2 mutant which binds more avidly to TREs was a more effective inhibitor of T3 action than wild type TR alpha 2. Together these data indicate that TR alpha 2 inhibits T3 action by competing for binding to TREs.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
identical protein binding  IPIThra_v1 (Rattus norvegicus)1580108homodimerizationRGD 
identical protein binding  IPIThra_v2 (Rattus norvegicus)1580108homodimerizationRGD 
protein homodimerization activity  IDA 1580108 RGD 
protein-containing complex binding  IDA 1580108heterodimerization and homodimerizationRGD 
protein-containing complex binding  IDA 1580108heterodimerizationRGD 
sequence-specific DNA binding  IDA 1580108; 1580108; 1580108 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Thra  (thyroid hormone receptor alpha)
Thra_v1  (thyroid hormone receptor alpha, variant 1)
Thra_v2  (thyroid hormone receptor alpha, variant 2)


Additional Information