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Thyroid hormone receptor homodimers can function as ligand-sensitive repressors
F J Piedrafita1, I Bendik, M A Ortiz
1San Diego Regional Cancer Center, La Jolla, California 92037, USA.
Molecular Endocrinology (Baltimore, Md.)
|May 1, 1995
Summary
Thyroid hormone receptors (TRs) can bind DNA as homodimers without retinoid X receptors (RXRs). This TR homodimer binding acts as a ligand-sensitive repressor, revealing crucial regulatory functions independent of RXRs.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Nuclear Receptors
Background:
- Thyroid hormone receptors (TRs) typically heterodimerize with retinoid X receptors (RXRs) for DNA binding.
- Steroid hormone receptors bind response elements as homodimers, unlike TRs.
Purpose of the Study:
- To compare TR DNA binding and gene regulation with and without RXR.
- To investigate the role of TR homodimers in gene regulation.
Main Methods:
- Analysis of TR DNA binding affinity.
- Assessment of gene-regulatory characteristics in the presence and absence of RXR.
- Examination of TR beta mutants and v-erbA oncogene activity.
Main Results:
- TRs bind as homodimers to specific thyroid hormone response elements (e.g., inverted palindromes of AGGTCA motifs) without RXR.
- Thyroid hormone (T3) inhibits TR homodimer binding, preventing ligand-dependent activation.
- TR homodimers function as potent ligand-responsive repressors, especially at sites 3' of the TATA box.
- Naturally occurring TR beta mutants and v-erbA oncogene show defects in this ligand-sensitive repression.
Conclusions:
- TRs possess significant regulatory functions independently of RXRs.
- Ligand-sensitive repression by TR homodimers is a critical regulatory mechanism.
- Defects in TR homodimer repression are linked to thyroid hormone resistance and oncogenesis.