Nucleic Acids Research, Vol 24, Issue 12 2252-2259, Copyright © 1996 by Oxford University Press
M Harbers, GM Wahlstrom and B Vennstrom
The thyroid hormone receptor (TR) regulates the transcription of its target
genes by interacting with specific hormone response elements consisting
usually of directly repeated half-sites with the consensus sequence AGGTCA.
To investigate the role of the spacer sequences separating the half-sites,
heterodimers formed by TRalpha and the retinoid-X receptor (RXR) were used
in a PCR based selection and amplification assay. The TRalpha/RXR
heterodimer selected for elements with directly repeated half-sites having
a spacer of 4 nucleotides (DR4). Preferences for nucleotides in the TR
binding half-site motif as well as for the 4 nucleotides separating the two
half-sites were found. DNA binding and transfection studies using DR4
elements with different spacer sequences showed the importance of these
nucleotides for the activity of the response element: some spacer sequences
allowed little or no transactivation from the element, whereas other
sequences supported strong transactivation. A pyrimidine nucleotide in
position three of the spacer enhanced TRalpha binding and transactivation.
Additional experiments showed that heterodimers between RXR and other
putative receptors exhibited a similar but distinct specificity for the
spacer sequence. Our results thus suggest that the four nucleotides
separating the two half-sites in hormone response elements have a major
role in determining induction of hormone responsive genes.
ARTICLES
Transactivation by the thyroid hormone receptor is dependent on the spacer sequence in hormone response elements containing directly repeated half-sites
Karolinska Institute, Medical Nobel Institute, Department of Cell and Molecular Biology, Laboratory of Developmental Biology, Stockholm, Sweden.
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