12.7 Regulation of Transcription by Nuclear Hormone Receptors in Chapter 12 Biochemical Signaling

12.7 Regulation of Transcription by Nuclear Hormone Receptors

The steroid, retinoic acid (retinoid), and thyroid hormones form a large group of receptor ligands that exert at least part of their effects by a mechanism fundamentally different from that of other hormones: they act directly in the nucleus to alter gene expression. We discuss their mode of action in detail in Chapter 28, along with other mechanisms for regulating gene expression. Here we give a brief overview.

Steroid hormones (estrogen, progesterone, vitamin D, and cortisol, for example), too hydrophobic to dissolve readily in the blood, are transported on specific carrier proteins from their point of release to their target tissues. In target cells, these hormones pass through the plasma membrane and nuclear membrane by simple diffusion and bind to specific receptor proteins in the nucleus (Fig. 12-34). Hormone binding triggers changes in the conformation of a receptor protein so that it becomes capable of interacting with specific regulatory sequences in DNA called hormone response elements (HREs), thus altering gene expression (see Fig. 28-34). The bound receptor-hormone complex enhances the expression of specific genes adjacent to HREs, with the help of several other proteins essential for transcription. Hours or days are required for these regulators to have their full effect — the time required for the changes in RNA synthesis and subsequent protein synthesis to become evident in altered metabolism.

A figure shows the general mechanisms by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression as a series of four steps. — FIGURE 12-34 General mechanism by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression. The details of transcription and protein synthesis are discussed in Chapters 26 and 27. Some steroids also act through plasma membrane receptors by a completely different mechanism.

An irregular plasma membrane runs from the middle left to upper right with the area below labeled as cytosol. A dashed line outlines the nucleus at the center left. Step 1: Hormone, carried to the target tissue on serum binding proteins, diffuses across the plasma membrane and binds to its specific receptor protein in the nucleus. A light red rectangular serum-binding protein with bound hormone has a small red almost rectangular hormone in a cutout on its bottom side. In step 1, the serum binding protein leaves and the hormone moves across the plasma membrane, then across the nuclear envelope. In step 2, a green nuclear receptor with a rounded rectangular half attached to a rounded half with a rounded cutout is joins the hormone. Step 2: Hormone binding changes the conformation of the receptor; it forms homo- or hetero-dimers with other hormone-receptor complexes and binds to specific regulatory regions called hormone response elements (H R Es) in the D N A adjacent to specific genes. A strand of D N A is shown as a line with a small blue piece to the left, then a long yellow piece labeled H R E that has two nuclear receptors attached to its right side by the bottom of their rounded ends. Each of these receptors has a hormone attached in the cutout on the upper side of its rounded end. To the right of the second receptor, the strand of D N A becomes blue and bends down to run vertically up through a channel in a round brown R N A polymerase molecule with a small strand extending to its lower left. An arrow points down past the number 3 and text reading to a green wavy strand of m R N A. Step 3: Receptor attracts coactivator or corepressor protein(s) and, with them, regulates transcription of the adjacent gene(s), increasing or decreasing the rate of m R N A formation. An arrow points from m R N A out of the nucleus to a strand of m R N A with a ribosome assembled around it. Text below the arrow reads, translation on ribosomes. The ribosome has a large rounded piece below with a white strand extending from it and a light almost rectangular piece above over the green m R N A. An arrow points from the ribosome past the number 4 to a light blue oval labeled new protein with an arrow pointing to text reading, altered cell function. Step 4: Altered levels of the hormone-regulated gene product produce the cellular response to the hormone.

The specificity of the steroid-receptor interaction is exploited in the use of the drug tamoxifen to treat breast cancer. In some types of breast cancer, division of the cancerous cells depends on the continued presence of estrogen. Tamoxifen is an estrogen antagonist; it competes with estrogen for binding to the estrogen receptor, but the tamoxifen-receptor complex has little or no effect on gene expression. Consequently, tamoxifen administered after surgery or during chemotherapy for hormone-dependent breast cancer slows or stops the growth of remaining cancerous cells. Another steroid analog, the drug mifepristone (RU486), binds to the progesterone receptor and blocks hormone actions essential to implantation of the fertilized ovum in the uterus, and thus functions as a contraceptive.

A figure shows the structures of tamoxifen and mifepristone (R U 486).

SUMMARY 12.7 Regulation of Transcription by Nuclear Hormone Receptors

Steroid hormones enter cells by simple diffusion and bind to specific receptor proteins, inducing a structural change that exposes a specific binding site on the DNA.
The hormone-receptor complex binds specific regions of DNA at the hormone response elements, and interacts with other proteins to regulate the expression of nearby genes.