Abstract
Thyroid hormone exerts its biological effect by binding
to a TR. Both liganded and unliganded TRs regulate the transcription of
T3-responsive genes. Cofactors with activating or repressing
function modulate the transcriptional regulation by TRs. We showed that
steroid receptor coactivator 1 (SRC-1)-deficient mice
(SRC-1−/−) exhibit partial resistance to thyroid
hormone at the level of the pituitary thyrotrophs. To determine whether
SRC-1 deficiency affects globally T3-dependent transcriptional
regulation, we studied the effects of thyroid hormone deprivation and
replacement on the expression of several genes in different tissues of
SRC-1−/− and wild-type mice
(SRC-1+/+). Thyroid hormone deficiency was induced by
a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk.
l-T3 was injected ip for the last 4 d in one group
(PTU+T3 group), and another group (PTU group) received only
vehicle. Levels of mRNAs for T3-responsive genes were determined
by Northern blotting: GH and TSHβ in pituitary; type 1 iodothyronine
5′-deiodinase, spot 14 (S14), and malic enzyme in liver; and
sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy
chain α and β in heart. Serum parameters, TSH, total cholesterol,
creatine kinase, and alkaline phosphatase (AP), were also
measured.
Hypothyroidism produced a comparable increase in TSHβ
mRNA in both genotypes, but its suppression by l-T3
was attenuated in SRC-1−/− mice. In contrast,
hypothyroidism failed to reduce S14 mRNA levels in
SRC-1−/− mice. As a consequence, the response to
l-T3 was not observed in these mice. SRC-1 deficiency
had no effect on the expression of the rest of the T3-responsive
genes examined. Of the four serum parameters, the T3-mediated
decrease in TSH and changes in AP were attenuated in
SRC-1−/− mice. We conclude that SRC-1 deficiency
altered the expression of only some of the T3-responsive genes.
SRC-1 appears to be involved not only in transcriptional activation by
liganded TRs, but also in the suppression by liganded or unliganded TRs.
Some of the effects of SRC-1 may be TR isoform
specific.