Activation of Progesterone and Androgen Receptors by Signal Transduction Pathways

Abstract

Progesterone receptors (PR) and androgen receptors (AR) are members of the steroid/thyroid hormone superfamily of ligand-activated transcription factors (Evans 1988). In common with other members of the family, they contain carboxyl terminal hormone-binding domains, amino terminal regions that are important for transcriptional activation, and DNA-binding domains that are located between the hormone-binding domain and transactivation region (Fawell et al. 1990; Tsai and O’Malley 1994). Although these receptors are activated by their cognate ligands, recent studies have shown that PR and AR also respond to signal transduction pathways by enhancing their ligand-dependent response; in some cases, they are activated in the absence of hormone. The ability to respond to alternate signaling pathways in the absence of hormone is not a uniform characteristic of steroid receptor family members. All of the estrogen receptors tested appear to be responsive under some conditions (Smith et al. 1993; Ignar-Trowbridge et al. 1992; Aronica and Katzenellenbogen 1991). However, whereas chicken (Denner et al. 1990b) and rodent (Turgeon and Waring 1994) PR are responsive, the human PR is generally not responsive (Beck et al. 1992). In the case of the androgen receptor, it appears that the human receptor will respond to specific activation pathways (Culig et al. 1994; Nazareth and Weigel 1996), but the rat receptor is unresponsive (Ikonen et al. 1994; Reinikainen et al. 1996). Finally, the glucocorticoid receptor requires a ligand for activation (Nordeen et al. 1993). The mechanism by which these receptors can be activated in the absence of ligand is a topic of active research.