The division of the family of nuclear receptors is based on structure and mechanism of action, with the first subfamily consisting of steroid hormone receptors and the second subfamily consisting of receptors that bind retinoic acid, thyroid hormones, and vitamin D. Ligand-receptor complex activation of these receptors results in the regulation of gene expression through the binding of transcription factors to DNA. The location of nuclear receptors varies, with glucocorticoid and mineralocorticoid receptors found in the cytoplasm and interacting with chaperones. Hormone binding causes a conformational change in the receptors, leading to dissociation of chaperones and translocation of the hormone-bound receptor complex to the nucleus. Estrogen and progesterone receptors are primarily located in the nucleus, while thyroid hormone and retinoic acid receptors are bound to DNA within the nucleus. Nuclear receptors bind to specific DNA sequences known as hormone response elements, resulting in a conformational change in DNA and initiation of transcription. In addition to their role as transcriptional activators, nuclear receptors can act as transcriptional repressors. For example, glucocorticoids suppress the expression of genes that cause inflammation. cAMP serves as an important second messenger and can stimulate transcription of various genes, including those coding for hormones. Genes activated by cAMP typically contain a cAMP response element in their DNA. PKA phosphorylates CREB, which increases its affinity for CREB-binding protein and activates transcription. The termination of the response occurs when PKA phosphorylates a phosphatase that dephosphorylates CREB. Growth factors such as EGF, PDGF, NGF, and insulin activate enzyme-linked receptors with tyrosine kinase activity. Activation of tyrosine kinases leads to the phosphorylation of the mitogen-activated protein kinase, which then translocates to the nucleus and stimulates the transcription of genes involved in cell growth. Tyrosine kinase-associated receptors, although lacking tyrosine kinase activity themselves, are associated with Janus family proteins that do possess tyrosine kinase activity. Once activated, hormone tyrosine kinase-associated receptors activate Janus family proteins, leading to the phosphorylation of signal transducers and activators of transcription. Phosphorylated STATs dimerize and enter the nucleus to regulate transcription.
The family of nuclear receptors includes more than 30 genes and has been divided into two subfamilies on the basis of structure and mechanism of action: (1) steroid hormone receptors and (2) receptors that bind retinoic acid, thyroid hormones (iodothyronines), and vitamin D. When ligands bind to these receptors, the ligand-receptor complex activates transcription factors that bind to DNA and regulate the expression of genes (see
Figs. 3.2B, 3.5, and 3.7
The location of nuclear receptors varies. Glucocorticoid and mineralocorticoid receptors are located in the cytoplasm, where they interact with chaperones (i.e., heat shock proteins; see
Fig. 3.2B ). Binding of hormone to these receptors results in a conformational change that causes chaperones to dissociate from the receptor, thereby revealing a nuclear localization motif that facilitates translocation of the hormone-bound receptor complex to the nucleus. Estrogen and progesterone receptors are located primarily in the nucleus, and thyroid hormone and retinoic acid receptors are located in the nucleus bound to DNA.
When activated by hormone binding, nuclear receptors bind to specific DNA sequences in the regulatory regions of responsive genes called hormone response elements. Ligand-receptor binding to DNA causes a conformational change in DNA that initiates transcription. Nuclear receptors also regulate gene expression by acting as transcriptional repressors. For example, glucocorticoids suppress the transcription activator protein-1 (AP-1) and nuclear factor κB, which stimulate the expression of genes that cause inflammation. By this mechanism glucocorticoids reduce inflammation.
As noted previously, cAMP is an important second messenger. In addition to its importance in activating PKA, which phosphorylates specific serine and threonine residues on proteins, cAMP stimulates the transcription of many genes, including those that code for hormones, including somatostatin, glucagon, and vasoactive intestinal polypeptide (see
Fig. 3.10 ). Many genes activated by cAMP have a cAMP response element (CRE) in their DNA. Increases in cAMP stimulate PKA, which not only acts in the cytoplasm but also can translocate to the nucleus, where it phosphorylates CREB and thereby increases its affinity for CREB-binding protein (CBP). The CREB-CBP complex activates transcription. The response is terminated when PKA phosphorylates a phosphatase that dephosphorylates CREB (see
Fig. 3.10).
Many growth factors, including EGF, PDGF, NGF, and insulin, bind to and activate enzyme-linked receptors that have tyrosine kinase activity. Activation of tyrosine kinases initiates a cascade of events that enhance the activity of the small GTP-binding protein Ras, which in a series of steps and intermediary proteins phosphorylates the mitogenactivated protein kinase, which then translocates to the nucleus and stimulates transcription of genes that stimulate cell growth.
Tyrosine kinase–associated receptors, as noted earlier, are activated by a variety of hormones, including cytokines, growth hormone, and interferon. Although these receptors do not have tyrosine kinase activity, they are associated with Janus family proteins, which do have tyrosine kinase activity. Once activated, hormone tyrosine kinase– associated receptors activate Janus family protein, which phosphorylates latent transcription factors called signal transducers and activators of transcription (STATs). When phosphorylated on tyrosine residues, STATs dimerize and then enter the nucleus and regulate transcription.