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.
For a steroid hormone to regulate (turn on or off) gene transcription, its receptor must:
- bind to the hormone (cortisol in the case of the glucocorticoid receptor)
- 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
- bind to other protein cofactors
This autoradiograph 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. 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 and estrogens
- the thyroid hormone, T3
- calcitriol, the active form of vitamin D
- retinoids: vitamin A (retinol) and its relatives
- retinoic acid (tretinoin — also available as the drug Retin-A®); and its isomer
- isotretinoin (sold as Accutane® for the treatment of acne).
- bile acids
- 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