Hormonal effects occurring via membrane receptors tend to be of short duration because they represent responses to rapid and urgent physiological demands and involve activation or inhibition of preexisting enzymes.

The effects of steroids involve longer-term changes, such as the conversion of a resting cell to a growing cell. Steroids and related hormones (i.e., thyroid, vitamin D, and retinoic acid hormones) act intracellularly, within the nucleus, where they regulate transcription of specific genes (usually positively). Table 23.6 lists several proteins whose synthesis is affected by these hormones.

Steroid and related hormones bind to specific receptor proteins in the cytosol. The receptor-hormone complexes dimerize and move into the nucleus, where they interact with specific DNA sequences called hormone-responsive elements (HREs).

cDNA sequence analysis of intracellular hormone receptors has revealed structural similarities among steroid receptors. Unambiguous identification of domains of function within the receptor molecule has also been performed. All of the known receptors in this family contain bound zinc, which is essential for DNA binding. Furthermore, the DNA-binding sequences show a completely conserved distribution of cysteine residues (Figure 23.16). Zinc atoms are probably complexed by the cysteine sulfurs in a pattern akin to the "zinc finger" structural motif of other eukaryotic transcriptional regulatory proteins (Figure 28.23, Figure 23.17).

The utility of a set of long-term-acting regulators is evident the estrogens and progesterone that regulate the female reproductive cycle. In humans these hormones interact over a 4-week cycle to prepare the uterus for implantation of a fertilized ovum.

The actions of glucocorticoids are comparable, in that control of the synthesis of particular proteins allows for long-term metabolic adaptation. Whereas estrogens exercise control of reproductive metabolism over a several-week period, the secretion of glucocorticoids is a means of adaptation to longer-term stress. This adaptation involves stimulation of gluconeogenesis and synthesis of a variety of proteins, including some that counteract the effects of inflammation. Unlike estrogens, which act chiefly in reproductive tissues, the glucocorticoids influence cells in a wide variety of target tissues. Glucocorticoids act to stimulate transcription of a protein called B, which inactivates the transcriptional factor called NF-B. NF-B helps control transcription of the cytokines, which stimulate the immune response (Figure 23.18).

The growth of some breast tumor cells is activated by estrogen. The drug, tamoxifen binds to estrogen receptors without activating estrogen-responsive genes. Tamoxifen treatment of patients with such tumors after surgery or chemotherapy often antagonizes estrogen binding in residual tumor cells and retards their growth. The drug, RU486, binds to progesterone receptors and blocks the events essential to implantation of a fertilized ovum in the uterus. Hence, RU486 is an effective contraceptive agent, even when taken after intercourse.

1. C2H2 Zinc Finger Proteins

2. Zinc Finger-Like Domains