Unliganded T3R, but not its oncogenic variant, v-erbA, suppresses RAR-dependent transactivation by titrating out RXR.
V-erbA is thought to be an antagonist of thyroid hormone receptor (T3R) function. Here we show that unliganded T3R, but not v-erbA, suppresses retinoic acid (RA)-dependent induction of the RAR-beta 2 promoter by competing for the common dimerization partner, the retinoid X receptor (RXR). Firstly, T3R suppression can be alleviated by co-transfection of RXR. Secondly, T3R, but not v-erbA, competes with RAR for RXR and causes the dissociation of a preformed RAR/RXR-RARE ternary complex in vitro. A single point mutation located in the dimerization interface of v-erbA (Pro349 to Ser) abolishes the transdominant phenotype when introduced at the respective position in T3R. The hypertransforming v-erbA variant r12, in which this mutation is reversed (Ser349 to Pro) suppresses RA-induced differentiation in chicken erythroid progenitors, while v-erbA does not. Our data thus suggest that unliganded T3R and v-erbA act as dominant suppressors through mechanistically distinct pathways.
Barettino
D
D
EMBL, Gene Expression Programme, Heidelberg, Germany.
Bugge
T H
TH
Bartunek
P
P
Vivanco Ruiz
M D
MD
Sonntag-Buck
V
V
Beug
H
H
Zenke
M
M
Stunnenberg
H G
HG
D001483:Base Sequence; D001667:Binding, Competitive; D002256:Carbonic Anhydrases / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D018774:Oncogene Proteins v-erbA; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D018774:Oncogene Proteins v-erbA; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D002256:Carbonic Anhydrases