Nongenotropic, Sex-Nonspecific Signaling through the Estrogen or Androgen Receptors

Abstract

The relationship of the classical receptors and their transcriptional activity 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 the ligand binding domain and eliminated by nuclear targeting of the receptor protein; ERalpha, ERbeta, or AR can transmit it with similar efficiency irrespective of whether the ligand is an estrogen or an androgen. This antiapoptotic action can be dissociated from the transcriptional activity of the receptor with synthetic ligands, providing proof of principle for the development of function-specific-as opposed to tissue-selective-and gender-neutral pharmacotherapeutics.

The mutual dependence between bone and gonads

“…This may be explained by the fact that in these models the levels of sex steroid hormones are abnormally high, and/or that these hormones may also have nongenomic modes of action. Androgen and estrogen can transmit antiapoptotic effects on osteoblasts in vitro with a similar efficiency via either AR or ERs, irrespective of whether the ligand is an androgen or an estrogen (Kousteni et al 2001, Manolagas et al 2002. Hence, at the present time the mechanisms mediating estrogen and androgen function in the bone, via ERs and AR, are not fully elucidated.…”

“…Furthermore, androgens stimulate the proliferation of osteoblast progenitors and the differentiation of mature osteoblasts ( Fig. 1; Kasperk et al 1989, Kousteni et al 2001, Manolagas et al 2002. At the molecular level, some evidence indicates that androgens favor osteoblast proliferation and differentiation (Fig.…”

Signaling via Shc family adapter proteins

“…Again little is known about the mechanism of Shc mediated regulation of Bcl-2 expression. Recently, a survival signal mediated via estrogen and androgen receptors that involves Shc has also been reported (Kousteni et al, 2001).…”

“…The 66 kDa isoform of ShcA is expressed in most cells except in the hematopoietic lineage and contains an additional amino-terminal CH-like region (denoted CH2) Pelicci et al, 1992; Figure 1). The tyrosine phosphorylation of Shc has been noticed upon engagement of numerous cell surface receptors such as growth factor receptors (Gelderloos et al, 1998;Pelicci et al, 1992;Pronk et al, 1994;Rozakis-Adcock et al, 1992;Sasaoka et al, 1994;Stephens et al, 1994;Yokote et al, 1994); antigen receptors (Ravichandran et al, 1993;Saxton et al, 1994); cytokine receptors (Burns et al, 1993;Damen et al, 1993;Lioubin et al, 1994;Matsuguchi et al, 1994;Pratt et al, 1996;Ravichandran and Burako , 1994;Velazquez et al, 2000); G-protein coupled receptors and hormone receptors (Erwin et al, 1995;Kousteni et al, 2001;Migliaccio et al, 1996;Morte et al, 1998). In addition, a role for Shc has been ascribed in transformation by the polyoma middle T antigen and BCR ± ABL (Campbell et al, 1994;Goga et al, 1995;Mullane et al, 1998;Puil et al, 1994;Zhu et al, 1998).…”

Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation

“…Estrogen actions can be exerted through either a genomic (transcription activation) or a nongenomic pathway, which involves putative membrane-bound receptors and activation of the Src/Shc/ERK signal transduction route (Coleman & Smith 2001, Kousteni et al 2001. Until now, it has been unclear to what extent the two pathways contribute to the regulation of longitudinal growth by E 2 .…”