37.3 Gene Expression Is Regulated by Hormones

Just as bacteria can adjust their patterns of gene expression in response to chemicals in their environment, eukaryotes have many systems for responding to environmental stimuli. As the first step in the control of gene expression, the initiation of transcription by RNA polymerase II is the focal point for many signal-transduction pathways. As an example, we will examine a system that detects and responds to estrogens. Synthesized and released by the ovaries, estrogens, such as estradiol, are cholesterol-derived steroid hormones. They are required for the development of female secondary sex characteristics and, along with progesterone, participate in the ovarian cycle.

Because they are hydrophobic signal molecules, estrogens easily diffuse across cell membranes. When inside a cell, estrogens bind to highly specific receptor proteins. Estrogen receptors are members of a large family of proteins that act as receptors for a wide range of hydrophobic molecules. The steroid receptors are different from the receptors discussed thus far in that they are soluble and located in the cytoplasm or nucleoplasm, rather than being bound to membranes. This receptor family includes receptors for other steroid hormones, such as the androgen testosterone, as well as thyroid hormones, and vitamin A-derivative retinoids. All these receptors, common in multicellular organisms, have a similar mode of action. On binding of the signal molecule (called, generically, a ligand), the ligand–receptor complex modifies the expression of specific genes by binding to control elements in the DNA. The human genome encodes approximately 50 members of this family, often referred to as nuclear hormone receptors.

Nuclear Hormone Receptors Have Similar Domain Structures

Nuclear hormone receptors bind to specific DNA sites referred to as response elements. In regard to the estrogen receptor, the estrogen response elements (EREs) contain the consensus sequence 5′-AGGTCANNNTGACCT-3′. As expected from the symmetry of this sequence, an estrogen receptor binds to such sites as a dimer.

A comparison of the amino acid sequences of members of the nuclear hormone-receptor family reveals two highly conserved domains: a DNA-binding domain and a ligand-binding domain (Figure 37.9). The DNA-binding domain lies toward the center of the primary structure and includes nine conserved cysteine residues. This domain provides these receptors with sequence-specific DNA-binding activity. Eight of the cysteine residues bind zinc ions to form DNA-binding domains that are called zinc-finger domains.

Figure 37.9: The structure of two nuclear hormone-receptor domains. Nuclear hormone receptors contain two crucial conserved domains: (1) a DNA-binding domain toward the center of the sequence and (2) a ligand-binding domain toward the carboxyl terminus. The structure of a dimer of the DNA-binding domain bound to DNA is shown, as is one monomer of the normally dimeric ligand-binding domain.

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The second highly conserved region of a nuclear hormone receptor lies near the carboxyl terminus. This area of the receptor forms a hydrophobic pocket that is the ligand-binding site. Ligand binding leads to substantial structural rearrangement (Figure 37.10). How does ligand binding by the receptor lead to changes in gene expression? Intuitively, we might think that ligand binding allows the receptor to bind to DNA. Interestingly, ligand binding has little effect on the ability of the receptor to bind its response element. Rather, ligand binding allows the receptor to recruit other proteins that facilitate transcription.

Figure 37.10: Ligand binding to nuclear hormone receptor. The ligand binding causes structural alteration in the receptor so that the hormone lies completely surrounded within a pocket in the ligand-binding domain. Notice that helix 12 (shown in purple) folds into a groove on the side of the structure on ligand binding.

Nuclear Hormone Receptors Recruit Coactivators and Corepressors

Although the receptor can bind DNA without a ligand, the receptor cannot serve its recruitment function without first binding the ligand. Proteins that bind to the receptor only after it has bound to the steroid are called coactivators. The site for the interaction between the nuclear hormone–receptor complex and the coactivators is fully formed only when the ligand is bound (Figure 37.11). These coactivators are referred to as the p160 family because of their size (∼160 kDa). Coactivators work in concert with other proteins to form large multicomponent complexes that modify chromatin and the transcription machinery to regulate gene expression.

Figure 37.11: Coactivator recruitment. The binding of ligand to a nuclear hormone receptor induces a conformational change in the ligand-binding domain. This change in conformation generates favorable sites for the binding of a coactivator.

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Although the estrogen receptor is inactive in the absence of estrogen, other members of the nuclear hormone-receptor family, such as the receptors for thyroid hormone and retinoic acid, repress transcription in the absence of ligand. This repression also is mediated by the ligand-binding domain. In their unbound forms, the ligand-binding domains of these receptors bind to corepressor proteins. Corepressors bind to a site in the ligand-binding domain that overlaps the coactivator binding site. Ligand binding triggers the release of the corepressor and frees the ligand-binding domain, enabling it to bind to a coactivator.

!quickquiz! QUICK QUIZ 2

Outline the mechanism of action of estradiol.

!clinic! CLINICAL INSIGHT: Steroid-Hormone Receptors Are Targets for Drugs

Molecules such as estradiol that bind to a receptor and trigger signaling pathways are called agonists. As discussed in Chapter 29, some athletes take natural and synthetic agonists of the androgen receptor, a member of the nuclear hormone-receptor family, because their binding to the androgen receptor stimulates the expression of genes that enhance the development of lean muscle mass. Referred to as anabolic steroids, such compounds used in excess have substantial negative side effects.

Other molecules bind to nuclear hormone receptors but do not effectively trigger signaling pathways. Such compounds are called antagonists and are, in many ways, like competitive inhibitors of enzymes. Some important drugs are antagonists that target the estrogen receptor. For example, tamoxifen and raloxifene are used in the treatment and prevention of breast cancer, because some breast tumors rely on estrogen-mediated pathways for growth. These compounds are sometimes called selective estrogen receptor modulators (SERMs).

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