Hormonal Regulation of Gene Expression 
William W. Chin, M.D. — Investigator 
Dr. Chin is also Associate Professor of Medicine at Harvard Medical School and Senior Physician at 
Brigham and Women's Hospital, Boston. He obtained his undergraduate degree in chemistry from 
Columbia College and his M.D. degree from Harvard Medical School. His postdoctoral work was performed 
with Jacob Maizel and Philip Leder at NIH and with Joel Habener at Massachusetts General Hospital, 
Boston. His awards include the Bowditch Lectureship Award of the American Physiological Association, 
the Van Meter- USV Award of the American Thyroid Association, and the Outstanding Investigator's Award 
from the American Federation for Clinical Research. 
HORMONES, key players in the endocrine and 
nervous systems, are produced by special- 
ized tissues in the body, effect extracellular com- 
munication, and regulate cellular function. Our 
recent studies have considered the molecular 
mechanisms of gene regulation by a specific hor- 
mone, thyroid hormone. 
Thyroid Hormone Action 
Our early work has focused on the regulation 
of the thyrotropin (thyroid-stimulating hormone 
[TSH]) subunit genes by thyroid hormones. TSH is 
a polypeptide hormone that is produced and se- 
creted by a single cell type in the anterior pitu- 
itary gland. It comprises two different sugar- 
containing polypeptide subunits, a and /?, which 
are encoded by genes located on different chro- 
mosomes. Importantly, TSH stimulates the thy- 
roid gland to produce the thyroid hormones, T3 
and T4. These modified amino acids regulate me- 
tabolism and gene expression in almost every cell 
of the body. To maintain a constant level of T3 and 
T4 in the bloodstream, these hormones act back 
on the pituitary to decrease TSH production, in- 
cluding subunit gene expression, and secretion. 
Hence TSH and thyroid hormones are involved in 
a classic negative-feedback regulatory system. 
To understand further the molecular mecha- 
nisms involved in the negative regulation of TSH 
synthesis by thyroid hormones at the transcrip- 
tion level, we have isolated and analyzed the 
genes encoding the a- and /5-subunits of TSH in 
the rat and identified putative thyroid hormone- 
responsive elements (TREs). These TREs, which 
mediate a negative regulation by the thyroid hor- 
mones and thyroid hormone receptors (TRs), 
contain several consensus TR-binding half-sites 
in a direct repeat orientation and are located im- 
mediately upstream of the TATA box (a-subunit) 
or near the start of transcription (TSH;3 subunit) . 
Multiple Thyroid Hormone Receptors 
and Other Nuclear Factors 
Thyroid hormones, in general, act at the cellu- 
lar level by entering the cell either as Tj or T4. T4 
may be converted to T3 in certain tissues, such as 
the pituitary. T3 then enters the nucleus, where it 
interacts with the TR, a protein encoded by the 
proto-oncogene c-erbA. The T3-TR complex then 
binds directly to cis-DNA elements within thyroid 
hormone-responsive genes to activate the appro- 
priate responses. 
The TRs are encoded by two genes, a and /3, 
each expressing at least two related molecules 
obtained by alternative promoter choice and 
splicing. The rat TRa gene encodes a bona fide 
TR, TRal , and a related but non-Tj-binding form, 
c-erhAa2. The rat TRjS gene encodes two func- 
tional TRs, TRjSl and TR/32, which are identical 
except for different regions amino terminal to the 
DNA-binding domain. Remarkably, TR/32 was 
most highly expressed in the pituitary gland. This 
observation has potential physiological relevance 
because of the major role of thyroid hormones in 
regulating important hormone genes in the pitu- 
itary, including TSH. The finding also stands in 
contrast to the general tissue distribution of the 
other receptor forms. 
We recently demonstrated the existence of an- 
other nuclear protein(s) that can augment the 
binding of TRs to various TREs. This ubiquitous 
60- to 65-kDa protein (TRAP; TR auxiliary pro- 
tein) interacts with TR to form a heterodimer and 
also binds specific sequences within the TRE. Sev- 
eral regions of the carboxyl-terminal or ligand- 
binding domain of the TR are important for this 
heterodimerization. Preliminary results show 
that the TR-TRAP interaction may be critical in 
thyroid hormone-mediated transactivation. Fur- 
thermore, the recent identification of the reti- 
noid X receptor as a potential TRAP by several 
groups fuels additional excitement in this area. 
In summary, the thyroid hormone receptor fam- 
ily is complex. At least three biologically active 
forms are expressed in a tissue-specific fashion, 
and another form may have an important role in 
modulating the effects of the others. Knowledge 
of the functions of these receptor isoforms and 
their interactions with other nuclear factors will 
be critical for our full understanding of thyroid 
hormone action. 
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