chapter 30
Endocrine Metabolism I: Introduction
A generic depiction of the mechanism of steroid hormone action (see text for details). [Reprinted with permission from
A. W. Norman and G. Liwack,
2nd ed. San Diego; Academic Press, 1997, p. 40.]
thyroid hormone, retinoic acid, and l ,25(OH)2 vitamin D
are all found in the nucleus.
Activation of the receptor occurs in steps 3 and 4. The
receptors exist in cells complexed with a dimer of heat-
shock protein (HSP, 90-kDa), which conserves the func-
tional status of the receptor molecule in the absence of
the hormone. In addition, HSPs may function to prevent
the unoccupied receptor from binding to DNA by mask-
ing the DNA binding domain. HSPs bound to the hormone
binding domain of the receptor are displaced by the hor-
mone for which the receptor is specific. Once formed,
steroid-receptor complexes aggregate into homodimers,
and in this form the receptor is said to be “activated.”
The activated cytoplasmic receptors are translocated via
a nucleopore to the nucleus (step 5). In step
, the ac-
tivated receptor triggers (or inhibits) transcription of the
hormone-regulated gene. In the event of mRNA produc-
tion, the newly synthesized mRNA is translocated to the
cytoplasm where it is translated (step 7). The biological
effect of the hormone reflects the function of the pro-
tein (e.g., enzyme, transporter, hormone, receptor), and
the duration of the effect is a function of the half-life
of the mRNA (minutes to hours) and of the protein (hours
to days).
The steroid receptor homodimer may also regulate gene
expression by interacting with transcription factors that are
associated with either the HRE or the promoter. By bind-
ing to certain transcription factors, the activated hormone
receptor may
1. Stimulate gene expression by removing an inhibitory
transcription factor;
2. Stimulate gene expression by facilitating the
activation of the promoter by a transciption factor; or
3. Inhibit gene expression by removing a stimulatory
transcription factor.
One important transcription factor with which steroid
receptors interact is AP-1
), which promotes the expression of genes in-
volved in cell proliferation. The growth-suppressing effect
of glucocorticoids is probably mediated by the binding
of the hormone-GR complex to one component of AP-1
(c-jun) which, in effect, removes the AP-1-mediated pro-
motion of cell proliferation. Another transcriptional fac-
tor involved in steroid hormone action is the
response element binding protein
(CREB), which me-
diates the genomic effects of peptide hormones that uti-
lize the cAMP second messenger system (see below). A
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