Nucleocytoplasmic shuttling

Transcription complex

FIGURE 13-15 Schematic model of estrogen receptor action. Although the ER is predominantly found in the cell nucleus, it constantly shuttles between the nucleus and cytoplasmic compartments. After the ER binds to the ligand, it then dissociates from the inactive hsp 90-ER complex and forms a homodimer, (ER)2. The liganded ER homodimer then seeks out estrogen-specific hormone response elements, SRE, and forms a DNA-receptor complex that, in some fashion, stabilizes the formation of a transcription complex (TC). The TC comprises RNA polymerase II (pol II), transcription factors IIA, IIB, IID, and HE/ F, and a TATA box, all of which are located on the promoter of the gene that will be transcribed. The A/B, C, and E shown on the receptor (top portion of figure) refer to the domains of the ER (see Figures 1-26 and 13-14). [For a detailed discussion, see Tsai, M.-J., and O'Malley, B. W. (1994). Molecular mechanisms of actions of steroid/thyroid receptor superfamily members. Ann. Rev. Biochem. 63,451-486.]

pression by the preovulatory levels of progesterone. Then, when the serum concentrations of estradiol fall, the nuclear levels of the estrogen receptor fall precipitously as a consequence of unopposed progesterone action. Thus, changes in the levels of the estrogen receptor are a balance between, first, the combined actions of the simultaneous presence of progesterone and estradiol and, second, the unopposed action of progesterone during estrogen withdrawal.

D. Estrogen and Progestin Antagonists

As a consequence of the emergence of a detailed understanding of how steroid hormones interact with receptors to regulate gene transcription (see Figures 141,10-14,10-26, and 13-15), a new field of research has emerged concerning the design of steroid hormone antagonists. Steroid antagonists can be either steroidal analogues or nonsteroidal compounds that selectively function as inhibitors of steroid hormone action. Table 13-7 summarizes some proposed mechanisms of action of antagonists of steroid hormones. Table 13-8 tabulates some examples of steroid antagonists for each class of classical steroid hormones. Two models, based on extensive studies of the progesterone and estrogen receptors, which provide a conceptual basis for the mode of action of steroid antagonists, are presented in Figure 13-20.

In the first model (Figure 13-20A), the antihormone is envisioned to interfere with the normal process of cycling of the unoccupied receptor-heat shock protein 90 (hsp 90) complex between the nuclear and cytoplasmic compartments. The consequence of the presence of the antihormone is that the receptor accumulates in the cytoplasm where it can become degraded.

The second model has as its basis the fact that a major consequence of hormone binding to the progesterone receptor is the induction of a conformational

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