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chapter 30

Endocrine Metabolism I: Introduction

FIGURE 30-4

A generic depiction of the mechanism of steroid hormone action (see text for details). [Reprinted with permission from

A. W. Norman and G. Liwack,

Hormones,

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

6

, 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

(accessory/auxiliary/adapter

protein-

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

cAMP

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