Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Binding, Competitive
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Carbonic Anhydrases / genetics
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Carrier Proteins / metabolism*
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Cell Differentiation
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DNA Mutational Analysis
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DNA-Binding Proteins / metabolism
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Erythroblasts / cytology
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Gene Expression Regulation
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In Vitro Techniques
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Ligands
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Molecular Sequence Data
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Mutation
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Oncogene Proteins v-erbA
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Receptors, Cell Surface / metabolism*
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone / metabolism*
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Recombinant Fusion Proteins / metabolism
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Regulatory Sequences, Nucleic Acid
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Retinoid X Receptors
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Retroviridae Proteins, Oncogenic / genetics
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Retroviridae Proteins, Oncogenic / metabolism*
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Transcription Factors*
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Transcriptional Activation*
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Tumor Cells, Cultured
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Ligands
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Oncogene Proteins v-erbA
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Receptors, Cell Surface
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Recombinant Fusion Proteins
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Retinoid X Receptors
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Retroviridae Proteins, Oncogenic
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Transcription Factors
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Carbonic Anhydrases