Steroid Hormone Receptors and their Response Elements

Steroid hormone receptors are proteins that have a binding site for a particular steroid molecule. Their response elements are DNA sequences that are bound by the complex of the steroid bound to its receptor.

The response element is part of the promoter of a gene. Binding by the receptor activates or represses, as the case may be, the gene controlled by that promoter.

It is through this mechanism that steroid hormones turn genes on (or off).

Link to general discussion of eukaryotic promoters and the transcription factors that control them.

This image (courtesy of P. B. Sigler) shows a stereoscopic view of the glucocorticoid response element (DNA, the double helix shown in yellow at the left of each panel) with the glucocorticoid receptor (a protein homodimer, right portion of each panel) bound to it.

The DNA sequence of the glucocorticoid response element is
5' AGAACAnnnTGTTCT 3'
3' TCTTGTnnnACAAGA 5'
where n represents any nucleotide. (Note the inverted repeats.)

The glucocorticoid receptor, like all steroid hormone receptors, is a zinc-finger transcription factor; the zinc atoms are the four yellow spheres. Each is attached to four cysteines (shown in dark green).

For a steroid hormone to turn gene transcription on, its receptor must:

bind to the hormone
bind to a second copy of itself to form a homodimer
be in the nucleus, moving from the cytosol if necessary
bind to its response element
activate other transcription factors to start transcription

Each of these functions depend upon a particular region of the protein (e.g., the zinc fingers for binding DNA). Mutations in any one region may upset the function of that region without necessarily interfering with other functions of the receptor.

Visual Evidence of Hormone Binding

This autoradiograph (courtesy of Madhabananda Sar and Walter E. Stumpf) shows the endometrial cells from the uterus of a guinea pig 15 minutes after an injection of radioactive progesterone. The radioactivity has concentrated within the nuclei of the endometrial cells as shown by the dark grains superimposed on the images of the nuclei. The same effect is seen when radioactive estrogens are administered.

The cells of the endometrium are target cells for both progesterone and estrogens, preparing the uterus for possible pregnancy. [Link to discussion]

Nontarget cells (e.g. liver cells or lymphocytes) show no accumulation of female sex hormones. Although their DNA contains the response elements, their cells do not have the protein receptors needed.

The Nuclear Receptor Superfamily

The zinc-finger proteins that serve as receptors for glucocorticoids and progesterone are members of a large family of similar proteins that serve as receptors for a variety of small, hydrophobic molecules. These include:

other steroid hormones like
- the mineralocorticoid aldosterone
- estrogens
the thyroid hormone, T₃
calcitriol, the active form of vitamin D
retinoids: vitamin A (retinol) and its relatives
- retinal
- retinoic acid (tretinoin — also available as the drug Retin-A®); and its isomer
- isotretinoin (sold as Accutane® for the treatment of acne).
fatty acids. These bind members of the superfamily called peroxisome-proliferator-activated receptors (PPARs). They got their name from their initial discovery as the receptors for drugs that increase the number and size of peroxisomes in cells.

In every case, the receptors consists of at least three functional modules or domains. From N-terminal to C-terminal, these are:

a domain needed for the receptor to activate the promoters of the genes being controlled
the zinc-finger domain needed for DNA binding (to the response element)
the domain responsible for binding the particular hormone as well as the second unit of the dimer.

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15 September 2005