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).
Figure 9.4.1: Stereoscopic view of the glucocorticoid response element courtesy of P. B. Sigler. This image 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.
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
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.
Positive and Negative Response Elements
Some of the hundreds of glucocorticoid response elements in the human genome activate gene transcription when bound by the hormone/receptor complex. Others inhibit gene transcription when bound by the hormone/receptor complex. Example: When the stress hormone cortisol — bound to its receptor — enters the nucleus of a liver cell, the complex binds to the positive response elements of the many genes needed for gluconeogenesis — the conversion of protein and fat into glucose resulting in a rise in the level of blood sugar. The negative response element of the insulin receptor gene thus diminishing the ability of the cells to remove glucose from the blood. (This hyperglycemic effect is enhanced by the binding of the cortisol/receptor complex to a negative response element in the beta cells of the pancreas thus reducing the production of insulin.)
Note that every type of cell in the body contains the same response elements in its genome. What determines if a given cell responds to the arrival of a hormone depends on the presence of the hormone's receptor in the cell.
Visual Evidence of Hormone Binding
Figure 9.4.2: Autoradiograph of Endometrial cell courtesy of Madhabananda Sar and Walter E. Stumpf
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