Thyroid hormones and their receptors in transcriptional regulation
Author: Andersson, Monika
Date: 1997-12-12
Location: Föreläsningssalen, CMB, Doktorsringen 4C
Time: 9.00
Abstract
Thyroid hormones and their receptors in transcriptional regulation
Monika Andersson
From the Department of Cell and Molecular Biology
The Medical Nobel Institute
Karolinska Institutet
S-17177 Stockholm, Sweden
The thyroid hormone receptors (TRs) are encoded by two genes, alpha and
ß,and belong to a family of hormone activated nuclear receptors. This
family includesthe receptors for retinoids and vitamin D3 as well as the
receptors for steroid hormones.Transcriptional control by hormone is
mediated through receptor binding to targetgene DNA and subsequent
control of gene regulation.
Here we have studied several aspects of gene regulation controlled by TR
and itsoncogenic counterpart P75gag-v-erbA, to gain insights into the
specificity in DNAbinding and into which domains of the receptor are
important for intracellular localizationand control of erythroid
differentiation.
The specificity of binding of TR to DNA regulatory response elements
(TREs) wastested with band shift analysis in the absence and presence of
thyroid hormones.TR interacts as a monomer or homodimer to form complexes
with direct repeat, palindromicand with everted repeat AGGTCA core
motifs. The thyroid hormones T3 and T4, but notT2, disrupt homodimer- and
increase monomer complexes bound to TREs. A TR conformationalchange
induced by T3 is detected in TR monomers and in TR which forms a
heterodimerwith RXR.
TR is unique within the superfamily of receptors by the ability to bind
responseelements with core motifs positioned in several different
configurations. TR bindingto direct repeat and palindromic TREs
containing O to 6 nucleotides between the coremotifs (spacer) was assayed
in band shift analyses. High affinity binding and lowoff rate was
observed for complexes containing TR on TREs with direct repeats
separatedby a spacer of 4 nucleotides and on a palindromic TRE without a
spacer.
The oncoprotein P75gag-v-erbA blocks TR-induced erythroid
differentiation. A numberof TR / P75gag-v-erbA chimeric proteins were
tested for their effects of differentiationand it was shown that the DNA
binding domain (DBD) of P75gag-v-erbA is essentialfor self renewal and to
keep cells undifferentiated.
TR is localized to the nucleus both in the presence and absence of
thyroid hormones.To define the regions important for nuclear localization
we determined the intracellularlocalization of TR, P75gag-v-erbA and
various N-terminal variants of TR by immunocytochemistryfollowing
transfection. The data show that the N-terminal first 12 amino acids ofTR
are essential for exclusive nuclear localization.
P75gag-v-erbA represses TR/T3 activated transcription. To pinpoint which
regionsin P75gag-v-erbA that are responsible for this, we expressed
P75gag-v-erbA and variousTR / P75gag-v-erbA chimeric receptors in cells
expressing high levels of endogenousTR. A chimeric receptor, containing
the DBD and the N-terminus from TR and the ligandbinding domain from
P75gag-v-erbA, was able to repress a TRE not regulated by P75gag-v-erbA.
Keywords: Thyroid hormone receptor, regulatory response element,
palindrome, directrepeat, everted repeat, DNA hinding domain,
P75gag-v-erbA, differentiation, nuclearlocalization, repression.
Stockholm 1997
ISBN 9 1-628-2744-8
Issue date: 1997-11-21
Publication year: 1997
ISBN: 91-628-2744-8
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