Structural features of thyroid hormone response elements that increase susceptibility to inhibition by an RTH mutant thyroid hormone receptor
| Autor: | G A Brent, P R Larsen, John W. Harney, Ann Marie Zavacki |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Chloramphenicol O-Acetyltransferase
medicine.medical_specialty Macromolecular Substances Molecular Sequence Data Mutant Drug Resistance Regulatory Sequences Nucleic Acid Retinoid X receptor Biology Transfection Cell Line Thyroid hormone receptor beta Endocrinology Internal medicine Consensus Sequence medicine Animals Humans Point Mutation Amino Acid Sequence Receptor Repetitive Sequences Nucleic Acid Gene Rearrangement Hormone response element Binding Sites Receptors Thyroid Hormone Thyroid hormone receptor Base Sequence Thyroid Recombinant Proteins Rats medicine.anatomical_structure Thyroid hormone receptor alpha Growth Hormone Mutagenesis Site-Directed Triiodothyronine Chickens |
| Zdroj: | Endocrinology. 137:2833-2841 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/endo.137.7.8770904 |
| Popis: | The chicken lysozyme silencer F2 (F2) thyroid hormone response element (TRE) contains an unusual everted palindromic arrangement, has a high affinity for thyroid hormone receptor (TR) homodimers, and is especially sensitive to dominant negative inhibition by, the T3 resistance (RTH) mutant TR beta P453H. We used various TREs and TR mutations to determine the mechanisms for this sensitivity. Changing the F2 orientation from an everted palindrome to a direct repeat with a 4-bp gap (DR+4) (F2-DR) decreased the sensitivity to inhibition at high T3 concentrations, while a loss of this sensitivity occurred with a palindromic arrangement of these same half-sites. F2 contains the dinucleotide TG 5' to each consensus half-site conforming to the optimal TR-binding octamer, YRRGGTCA. A T to A change in position 1 of both F2 half-sites markedly reduced T3-induction, yet only slightly reduced TR homodimer or TR-retinoid X receptor (RXR) heterodimer binding. The TR beta ninth heptad mutation, L428R, prevents TR heterodimerization with RXR and eliminates the inhibitory effect of the P453H mutant TR on the F2-DR, but not the F2 element. Structural features of a TRE that favor strong TR binding of both TR homodimers and TR-RXR heterodimers containing the mutant TR, such as the everted palindromic conformation or the optimal TR-binding consensus octamer, enhance the sensitivity of a TRE to inhibition by the mutant TR. Thus, both half-site orientation and sequence contribute to the sensitivity of a given TRE to dominant negative inhibition by a mutant TR. |
| Databáze: | OpenAIRE |
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