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Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action
Ist Teil von
American journal of physiology: endocrinology and metabolism, 2003-01, Vol.284 (1), p.E36-E46
Ort / Verlag
United States: American Physiological Society
Erscheinungsjahr
2003
Quelle
MEDLINE
Beschreibungen/Notizen
Departments of 1 Medicine and
2 Pathology, University of Chicago, Chicago, Illinois
60637; 3 Laboratoire de Biologie Moléculaire et
Cellulaire de l'Ecole Normale Supérieure de Lyon, 69364 Lyon, France; and 4 Department of Molecular and Cellular
Biology, Baylor College of Medicine, Houston, Texas 77030
Isoforms of the thyroid hormone
receptor ( TR ) and TR genes
mediate thyroid hormone action. How TR isoforms modulate
tissue-specific thyroid hormone (TH) action remains largely unknown.
The steroid receptor coactivator-1 (SRC-1) is among a group of
transcriptional coactivator proteins that bind to TRs, along with
other members of the nuclear receptor superfamily, and modulate the
activity of genes regulated by TH. Mice deficient in SRC-1 possess
decreased tissue responsiveness to TH and many steroid hormones;
however, it is not known whether or not SRC-1-mediated activation of
TH-regulated gene transcription in peripheral tissues, such as heart
and liver, is TR isoform specific. We have generated mice deficient in
TR and SRC-1, as well as in TR and SRC-1, and investigated
thyroid function tests and effects of TH deprivation and TH treatment compared with wild-type (WT) mice or those deficient in either TR or
SRC-1 alone. The data show that 1 ) in the absence of TR or TR , SRC-1 is important for normal growth; 2 ) SRC-1
modulates TR and TR effects on heart rate; 3 ) two new
TR -dependent markers of TH action in the liver have been identified,
osteopontin (upregulated) and glutathione S -transferase
(downregulated); and 4 ) SRC-1 may mediate the
hypersensitivity to TH seen in liver of TR -deficient mice.
knockout; resistance to thyroid hormone; thyrotropin