Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: Dissociation from transcriptional activity

The relationship of the classical receptors and their transcriptional activ ity to nongenotropic effects of steroid hormones is unknown. We demonstrate herein a novel paradigm of sex steroid action on osteoblasts, osteocytes, embryonic fibroblasts, and HeLa cells involving activation of a Src/Shc/ERK signaling pathway and attenuating apoptosis. This action is mediated by th e ligand binding domain and eliminated by nuclear targeting of the receptor protein; ER alpha, ER beta, or AR can transmit it with similar efficiency irrespective of whether the ligand is an estrogen or an androgen. This anti apoptotic action can be dissociated from the transcriptional activity of th e receptor with synthetic ligands, providing proof of principle for the dev elopment of function-specific-as opposed to tissue-selective-and gender-neu tral pharmacotherapeutics.