Regulation of Gene Expression in Eukaryotes:- Eukaryotic Gene Expression Can Be Regulated by Intercellular and Intracellular Signals
The effects of steroid hormones (and of thyroid and retinoid hormones, which have the same mode of action) provide additional well-studied examples of the modulation of eukaryotic regulatory proteins by direct interaction with molecular signals . Un like other types of hormones, steroid hormones do not have to bind to plasma membrane receptors. Instead, they can interact with intracellular receptors that are themselves transcriptional transactivators. Steroid hormones too hydrophobic to dissolve readily in the blood (estrogen, progesterone, and cortisol, for example) travel on specific carrier proteins from their point of re lease to their target tissues. In the target tissue, the hormone passes through the plasma membrane by simple diffusion and binds to its specific receptor protein in the nucleus. The hormone-receptor complex acts by bind ing to highly specific DNA sequences called hormone response elements (HREs), thereby altering gene ex pression. Hormone binding triggers changes in the con formation of the receptor proteins so that they become capable of interacting with additional transcription fac tors. The bound hormone-receptor complex can either enhance or suppress the expression of adjacent genes. The DNA sequences (HREs) to which hormone receptor complexes bind are similar in length and arrangement, but differ in sequence, for the various steroid hormones. Each receptor has a consensus HRE sequence (Table 28–4) to which the hormone-receptor complex binds well, with each consensus consisting of two six-nucleotide sequences, either contiguous or separated by three nucleotides, in tandem or in a palindromic arrangement. The hormone receptors have a highly conserved DNA-binding domain with two zinc fingers (Fig. 1). The hormone-receptor complex binds to the DNA as a dimer, with the zinc finger domains of each monomer recognizing one of the six-nucleotide sequences. The ability of a given hormone to act through the hormone-receptor complex to alter the expression of a specific gene depends on the exact sequence of the HRE, its position relative to the gene, and the number of HREs associated with the gene.
Unlike the DNA-binding domain, the ligand-binding region of the receptor protein—always at the carboxyl terminus—is quite specific to the particular receptor. In the ligand-binding region, the glucocorticoid receptor is only 30% similar to the estrogen receptor and 17% similar to the thyroid hormone receptor. The size of the lig and-binding region varies dramatically; in the vitamin D receptor it has only 25 amino acid residues, whereas in the mineralocorticoid receptor it has 603 residues. Mutations that change one amino acid in these regions can result in loss of responsiveness to a specific hormone.
FIGURE 1 Typical steroid hormone receptors. These receptor proteins have a binding site for the hormone, a DNA-binding domain, and a region that activates transcription of the regulated gene. The highly conserved DNA-binding domain has two zinc fingers. The sequence shown here is that for the estrogen receptor, but the residues in bold type are common to all steroid hormone receptors.
Some humans unable to respond to cortisol, testosterone, vitamin D, or thyroxine have mutations of this type.
