Endocrine Glands 325thyroid also secretes a small amount of triiodothyronine, or T 3.
The carrier proteins have a higher affinity for T 4 than for T 3 , how-
ever, and, as a result, the amount of unbound (or “free”) T 3 in the
plasma is about 10 times greater than the amount of free T 4.
Approximately 99.96% of the thyroxine in the blood is
attached to carrier proteins in the plasma; the rest is free. Only
the free thyroxine and T 3 can enter target cells; the protein-bound
thyroxine serves as a reservoir of this hormone in the blood (this
is why it takes a couple of weeks after surgical removal of the
thyroid for the symptoms of hypothyroidism to develop). Once
the free thyroxine passes into the target cell cytoplasm, it is
enzymatically converted into T 3. As discussed in section 11.1, it
is the T 3 rather than T 4 that is active within the target cells.
Unlike the steroid hormone receptor proteins, the thyroid
hormone receptor proteins are located in the nucleus bound to
DNA (see fig. 11.7 ) even in the absence of their thyroid hor-
mone ligand. The thyroid hormone response element of DNA
has two half-sites, but unlike the case with the steroid recep-
tors, the thyroid hormone receptor (for T 3 ) binds to only one
of the half-sites. The other DNA half-site binds to the receptor
for a vitamin A derivative, 9- cis -retinoic acid. When the thy-
roid hormone receptor (abbreviated TR ) and the 9- cis -retinoic
acid receptor (abbreviated RXR ) bind to the two DNA half-
sites of the hormone response element, the two receptors form
a heterodimer. This term is used because these are different
receptors (in contrast to the homodimer formed by two steroid
hormone receptors on their DNA half-sites).
In the absence of their thyroid hormone ligand (T 3 ), the thy-
roid receptors recruit corepressor proteins that inhibit genetic
transcription. Thus, although the TR and RXR are bound to
DNA, the hormone response element is inhibited. When the
thyroid receptor binds to its T 3 ligand, the corepressor proteins
are removed and degraded by proteosomes (chapter 3), while
coactivator proteins are recruited. Thus, the nuclear receptor
proteins for thyroid hormone cannot stimulate genetic tran-
scription until they bind to their hormone ligands.
The T 3 may enter the cell from the plasma, but mostly it is
produced in the cell by conversion from T 4. In either case, it uses
some nonspecific binding proteins in the cytoplasm as “stepping
stones” to enter the nucleus, where the T 3 binds to the ligand-
binding domain of the receptor ( fig. 11.6 ). Once this occurs, the
receptor changes shape, enabling the removal of corepressor
proteins and the recruitment of coactivator proteins that promote
genetic transcription. The production of specific mRNA then
codes for the synthesis of specific enzyme proteins that change
the metabolism of the target cell ( figs. 11.6 and 11.7 ).
This pattern of regulation is similar for other nuclear
receptors that form heterodimers with the RXR. For example,
the receptor for 1,25-dihydroxyvitamin D 3 , the active form of
vitamin D, also forms heterodimers with the receptor for 9- cis -
retinoic acid (the RXR receptor) when it binds to DNA and
activates genes. The RXR receptor and its vitamin A deriva-
tive ligand thus form a link between the mechanisms of action
of thyroid hormone, vitamin A, and vitamin D, along with
those of some other molecules that are important regulators of
genetic expression.such as tamoxifen (see the next Clinical Application box) that
act like estrogen in one organ while antagonizing the action
of estrogen in another organ. Study of tamoxifen and other
selective estrogen receptor modulators (SERMs) has revealed
that estrogen action requires more than 20 different regulatory
proteins—called coactivators and corepressors —in addition
to the estrogen receptor. Coactivators and corepressors activate
or repress specific transcription factors (proteins that regulate
genetic transcription) but do not themselves bind to DNA. The
coactivators and corepressors in this case bind to specific pock-
ets for them in the estrogen receptor, which are separate from the
hormone binding sites (ligand binding domains). By this means,
the coactivators and corepressors promote or inhibit the ability
of estrogen to stimulate genetic transcription. SERMs can have
different effects in different organs because, even though they
bind to the estrogen receptor, they may enlist coactivator pro-
teins in one organ but not in another organ.
When a steroid hormone ligand binds to its nuclear recep-
tor protein (at the ligand-binding domain, fig. 11.5 ), it changes
the receptor protein structure. This causes (1) removal of a
group of proteins (called heat shock proteins ) that prevent the
receptor from binding to DNA, and (2) recruitment of coacti-
vator proteins, while corepressor proteins are prevented from
binding to the receptor. The coactivator proteins form a com-
plex that modifies the structure of the chromatin and facilitates
DNA transcription (that is, RNA synthesis) at the hormone
response element of DNA. As a result, the cell is stimulated to
produce particular proteins by the steroid hormone.
CLINICAL APPLICATION
About 75% of breast cancers test positive for the estrogen
receptor ( ER ), and so are stimulated to grow by estrogen.
For that reason, the standard treatment for postmenopausal
breast cancer patients who are ER positive, and as an auxil-
iary treatment for premenopausal patients, is an aromatase
inhibitor —a drug that blocks the ability of aromatase to con-
vert testosterone into estradiol (see fig. 11.2 ). Premenopausal
patients who are ER positive generally receive tamoxifen —
a selective estrogen receptor modulator ( SERM ). As a
SERM, tamoxifen has an anti-estrogenic effect in the breast,
but promotes estrogen actions on bone and the endometrium
of the uterus. In addition to the ER receptor, about 20% of
breast cancers are positive for the HER2/neu receptor (which
promotes the action of a cytokine, epidermal growth factor),
and can be treated with a monoclonal antibody (chapter 15,
section 15.4) called Herceptin that blocks this receptor.Mechanisms of Thyroid Hormone Action
As previously discussed, the major hormone secreted by the
thyroid gland is thyroxine, or tetraiodothyronine (T 4 ). Like ste-
roid hormones, thyroxine travels in the blood attached to carrier
proteins (primarily to thyroxine-binding globulin, or TBG ). The