Members of the nuclear receptor superfamily, which includes the steroid hormone (glucocorticoids, mineralocorticoids, androgens, and estrogens), vitamin D, retinoic acid, and thyroid hormone receptors, function as STF. These intracellular receptors contain a ligand-binding domain along with domains for DNA-binding and transcriptional activation. The ligand-binding domain is where the steroid hormone cortisol (a glucocorticoid) binds to the intracellular receptors. This binding leads to a conformational change in the receptor, activating it. The activated receptor-hormone complex enters the nucleus, dimerizes, and binds to DNA at a regulatory element called the glucocorticoid response element (GRE), which is an example of a hormone response element (HRE). By binding to the GRE, the receptor-hormone complex allows for the recruitment of coactivators to the transcriptional activation domain (TAD), resulting in the expression of cortisol-responsive genes. Each cortisol-responsive gene has its own GRE, allowing for the coordinate expression of a group of target genes, even if they are located on different chromosomes. The GRE can be found upstream or downstream of the genes it regulates and can be located at significant distances from them. The GRE functions as an enhancer, and if associated with repressors, the hormone-receptor complex can inhibit transcription.

Cell-surface receptors, on the other hand, include receptors for insulin, epinephrine, and glucagon. For instance, glucagon, a peptide hormone, binds to its G protein-coupled receptor on glucagon-responsive cells located on the plasma membrane. This binding triggers a signal transduction pathway that involves the production of intracellular cyclic adenosine monophosphate (cAMP), a second messenger. The rise in cAMP levels can impact protein expression and activity through the phosphorylation mediated by protein kinase A. Upon an increase in cAMP, a trans-acting factor called cAMP response element-binding (CREB) protein is phosphorylated and activated. The active CREB protein binds to a cis-acting regulatory element known as the cAMP response element (CRE) via a leucine zipper motif, resulting in the transcription of target genes containing CRE in their promoters. This system, involving cAMP/CRE/CREB, is responsible for upregulating certain genes, such as the genes for phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, which are essential enzymes involved in gluconeogenesis.

The processing and utilization of eukaryotic mRNA involve several steps. Before being exported from the nucleus to the cytoplasm for protein synthesis, eukaryotic mRNA undergoes capping at the 5'-end, polyadenylation at the 3'-end, and splicing. These processing events are crucial for the production of functional eukaryotic mRNA from pre-mRNA. Variations in splicing and polyadenylation can impact gene expression. Additionally, the stability of the messenger RNA also plays a role in gene expression.

Alternative splicing is a process that allows the generation of tissue-specific protein isoforms from the same pre-mRNA. It involves exon skipping, intron retention, and the usage of alternative splice-donor or -acceptor sites. For instance, tropomyosin (TM) pre-mRNA undergoes tissue-specific alternative splicing, leading to the production of multiple TM isoforms. It is worth noting that over 90% of all human genes undergo alternative splicing.
Intracellular receptors: Members of the nuclear receptor superfamily, which includes the steroid hormone (glucocorticoids, mineralocorticoids, androgens, and estrogens), vitamin D, retinoic acid, and thyroid hormone receptors, function as STF. In addition to domains for DNA-binding and transcriptional activation, these receptors also contain a ligand-binding domain. For example, the steroid hormone cortisol (a glucocorticoid) binds intracellular receptors at the ligand-binding domain (Fig. 33.10). Binding causes a conformational change in the receptor that activates it. The receptor– hormone complex enters the nucleus, dimerizes, and binds via a zinc finger motif to DNA at a regulatory element, the glucocorticoid response element (GRE) that is an example of a HRE. Binding allows recruitment of coactivators to the TAD and results in expression of cortisol-responsive genes, each of which is under the control of its own GRE. Binding of the receptor–hormone complex to the GRE allows coordinate expression of a group of target genes, even though these genes are on different chromosomes. The GRE can be located upstream or downstream of the genes it regulates and at great distances from them. The GRE, then, can function as a true enhancer (see p. 440). [Note: If associated with repressors, hormone–receptor complexes inhibit transcription.] b.
Cell-surface receptors: These receptors include those for insulin, epinephrine, and glucagon. Glucagon, for example, is a peptide hormone that binds its G protein–coupled plasma membrane receptor on glucagon-responsive cells. This extracellular signal is then transduced to intracellular cAMP, a second messenger (Fig. 33.11; also see Fig. 8.7 on p. 95), which can affect protein expression (and activity) through protein kinase A–mediated phosphorylation. In response to a rise in cAMP, a trans-acting factor (cAMP response element–binding [CREB] protein) is phosphorylated and activated. Active CREB protein binds via a leucine zipper motif to a cis-acting regulatory element, the cAMP response element (CRE), resulting in transcription of target genes with CRE in their promoters. [Note: The genes for phosphoenolpyruvate carboxykinase and glucose 6phosphatase, key enzymes of gluconeogenesis (see p. 122), are examples of genes upregulated by the cAMP/CRE/CREB system.]
B. Messenger RNA processing and use
Eukaryotic mRNA undergoes several processing events before it is exported from the nucleus to the cytoplasm for use in protein synthesis. Capping at the 5′-end (see p. 441), polyadenylation at the 3′-end (see p. 442), and splicing (see p. 442) are essential for the production of a functional eukaryotic messenger from most pre-mRNA. Variations in splicing and polyadenylation can affect gene expression. In addition, messenger stability also affects gene expression.
1.
Alternative splicing: Tissue-specific protein isoforms can be made from the same pre-mRNA through alternative splicing, which can involve exon skipping (loss), intron retention, and use of alternative splice-donor or -acceptor sites (Fig. 33.12). For example, the pre-mRNA for tropomyosin (TM) undergoes tissue-specific alternative splicing to yield a number of TM isoforms (see p. 443). [Note: Over 90% of all human genes undergo alternative splicing.] 2.