section 30.5
Types of Hormone Receptors
Thyroid hormone, 1,25-dihydroxy vitamin D, and retinoic acid receptor regulation of transcription. The hormone
receptor (HR) is dimerized at site (3) and is bound to DNA at hormone response element site (2). Without the ligand,
transcription is inactive due to the interaction of HR with corepressor at site 4. When the ligand (hormone) binds to HR,
the bound corepressor dissociates leading to an interaction between the coactivator and HR. These regulatory changes
result in increased transcription.
that is unbound at any given instant is accessible for
cellular “uptake,” i.e., the diffusional passage of the hy-
drophobic hormone through the lipid matrix of the cell
membrane and into the cell. Once in the cell, the hormone
associates loosely with cytoplasmic proteins that prevent
its escape back into plasma. Microsomal 5'-deiodinase,
which is present in thyroid target cells, catalyzes the re-
moval of the 5'-iodine from T4, converting it to T3. This
creates a concentration gradient that favors the movement
of hormone into the nuclear compartment, in which TR
(monomer or dimers) exists in association with the TRE
sequence of DNA. Monomeric TR appears to bind to a
TRE half-site, while dimeric (homodimer or heterodimer)
TR binds to two half-sites. When activated by T
ing to TR, the TRE promotes transcription of the gene
into hnRNA. After removal of the introns from hnRNA,
the resultant mRNA is translated into a protein at the
ribosomes. The protein, which may be regulatory or struc-
tural, is the final molecular expression of thyroid hormone
The outcome of T
binding to TR is not a stimulation of
transcription in all cases. In the pituitary thyrotrophs, T
inhibits transcription of both the TSH-a and TSH-/3 genes
by binding to TR-TRE complexes. The TR mediating this
inhibitory effect appears to be a monomer that binds to
a TRE half-site, in contrast to the usual dimeric TR that
binds to two TRE half-sites and mediates the stimulatory
effects of T
on transcription in other cell types.
In some instances, the actual cell response to thyroid
hormone is a manifestation of the activity of the induced
protein; therefore, the induced protein would first need to
be activated (e.g., by phosphorylation) before the thyroid
hormone effect on the cell can be seen.
Steroid Hormone Receptors
Steroid hormone receptors
belong to a large family of
DNA-binding proteins that include receptors for thyroid
hormone, retinoic acid, and l,25(OH)2 vitamin D. There
are specific receptors for glucocorticoids (GRs), mineralo-
corticoids (MRs), estrogens (ERs), androgens (ARs), and
progestogens (PRs), all of which are coded for by different
genes. Unlike the TR, there appears to be only one func-
tional receptor protein for a given steroid that is encoded on
a single gene. Like the TR, the steroid receptor is a single
protein with three regions (domains): a carboxy terminal
region that binds the steroid specifically, a central DBD,
and an amino terminal region that may function as a gene
enhancer. The DBD of the steroid receptor projects two
zinc fingers that allows both recognition of and binding to
the hormone response element (HRE) of DNA.
A generic depiction of the mechanism for steroid hor-
mone activity at a target cell is shown in Figure 30-4. The
first step consists of dissociation of the hormone from the
plasma transport protein and entry into the cell by diffu-
sion across the plasma membrane. In the second step the
hormone binds with the receptors in the cytoplasm and
nucleus. Receptors for glucocorticoid and aldosterone are
found in the cytoplasm and receptors for estrogen and pro-
gesterone are found in the nucleus. Recall that receptors for
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