17β-Estradiol-Dependent Activation of Signal Transducer and Activator of Transcription-1 in Human Fetal Osteoblasts Is Dependent on Src Kinase Activity

Abstract

Estrogen is essential for normal growth and remodeling of bone. Although the mechanism of estrogen action on bone cells has been widely investigated, the full spectrum of signal transduction pathways activated by estrogen is unknown. In this report, we investigate the effects of the gonadal hormone 17beta-estradiol on the regulation of signal transducer and activator of transcription-1 (Stat1) protein in cultured human fetal osteoblast cells, devoid of the classical estrogen receptors (ERs). 17beta-estradiol (10 nM) led to rapid (within 15 min) activation of Stat1 protein as indicated by increases in tyrosine phosphorylation and DNA binding activity. Also, 17beta-estradiol increased gamma-activated sequence-dependent transcription in transient transfection assays, suggesting an increase in Stat protein-dependent transcription. Estrogen-dependent Stat1 activation was blocked in cells that transiently express dominant-negative Stat1 mutant protein. Activation of Stat1 by 17beta-estradiol was not inhibited by ER antagonist ICI 182,780, providing further evidence that it is not dependent on classical ERs. 17beta-Estradiol induced rapid (within 15 min) Stat1 phosphorylation and stimulated gamma-activated sequence-dependent transcription in ER-negative breast cancer cells, indicating that these results are not unique to bone cells. The rapid estrogenic effect involving the phosphorylation and activation of Stat1 was blocked in the presence of Src family kinase inhibitor PP2; activated Stat1 was associated with Src protein in estrogen-treated cells. These findings indicate the requirement for Src kinase pathways in estrogen-mediated Stat1 activation. Thus, the ER-independent activation of Stat1 in 17beta-estradiol-treated osteoblast and breast cancer cells may partially mediate the actions of estrogen on target cells.

17 Beta-Estradiol Differentially Affects Left Ventricular and Cardiomyocyte Hypertrophy Following Myocardial Infarction and Pressure Overload

“…However, in cultured osteoclasts, estrogen rapidly induces Stat1 tyrosine phosphorylation and DNA binding in a manner dependent on Src kinase. [21] Similar findings have been reported in endothelial cells. [22] Elucidation of the precise molecular mechanisms that underlie the differential effects of E2 on Stat3 activation and myocyte hypertrophy following MI or TAC will require further investigation.…”

Estrogen Signaling Multiple Pathways to Impact Gene Transcription

“…Src, Shc, proline-, glutamic acid-, leucine-rich protein /modulator of non-genomic activity of estrogen receptor (PELP1/MNAR), the p85 subunit of PI3K, receptor tyrosine kinases (i.e., EGF and IGF-1 receptors), as well as G-protein isoforms (i.e., G s and G q) have all been reported to serve as components of large complexes of interacting proteins. Through the mediation of these molecules, E2 activates the MAPK and PI3K/AKT pathways [16,136,[149][150][151].…”

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

“…Interestingly, STAT1 induction by the EGFR-SRC axis is linked to induction of the STAT1 target gene IRF1, growth arrest, and apoptosis [14,15]. The gonadal hormone estrogen also activates STAT1 phosphorylation and target gene activation rapidly, dependent on Src kinase and independent of classical estrogen receptor signaling [16].…”