Hormonal Regulation of Gene Expression 
major role of thyroid hormones in regulating im- 
portant hormone genes in the pituitary, includ- 
ing TSH. The finding also stands in contrast to the 
general tissue distribution of the other receptor 
forms. 
In addition, we wished to determine how these 
trans-acting factors, of which TRs represent pro- 
totypes, are themselves regulated. We have 
shown that thyroid hormones regulate TR mRNAs 
in a complex and a tissue-specific manner in vivo 
and in vitro. The TR/32 mRNA is the most regu- 
lated form: in a 24-hour period, thyroid hor- 
mones decrease TR|82 mRNA to less than 1 0 per- 
cent of basal levels in the pituitary gland. In 
contrast, TRal and c-erbAa2 mRNAs are mod- 
estly suppressed, while TRjSl mRNA is not nega- 
tively regulated by thyroid hormones. 
In addition, we have observed an interesting 
feature of the a gene — that the strand opposite 
the one that encodes TRal and c-erbAal (pro- 
duced by alternative splicing of a single a tran- 
script) encodes a novel member of the c-erbA 
(thyroid hormone/steroid hormone) supergene 
family, called Rev erbAa. The predicted protein 
is more related to thyroid hormone and retinoic 
acid than the steroid hormone receptors. The 
mRNA of Rev erbAa shares a common 269-base 
pair exonic region with that of c-erbAa2. This 
unusual genomic arrangement, which is con- 
served among several mammalian species, sug- 
gests possible interregulation of the TRa and Rev- 
erbAa at the post-transcriptional levels. 
Finally, we have recently demonstrated the ex- 
istence of TRAP (TR auxiliary protein) , a nuclear 
protein that can augment the binding of TRs to 
various TREs. This ubiquitous 60- to 65-kDa pro- 
tein dimerizes with TRs to form a heterodimer 
and also binds specific sequences within the TRE. 
The full nature of TRAP and its role in thyroid 
hormone action remains to be determined. 
Thus the thyroid hormone receptor family is 
complex. There are at least three biologically ac- 
tive forms expressed in a tissue-specific fashion 
and another form that may have an important role 
in modulating the effects of the others. A knowl- 
edge of the functions of these different forms and 
their interaction with other nuclear factors will 
be critical for our full understanding of thyroid 
hormone action. 
Summary 
Our work has focused on the molecular mecha- 
nisms involved in the regulation of TSH gene ex- 
pression by thyroid hormones, including the cis 
elements and trans factors that are involved in 
this process. We hope that our efforts will pro- 
vide insight into the hormonal regulation of gene 
expression and cellular function in normal and 
pathologic endocrine states and in cancer. 
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