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This version published online on October 7, 2004
Endocrinology, doi:10.1210/en.2004-0486
A more recent version of this article appeared on January 1, 2005
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*Compound via MeSH
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*ESTRADIOL

Submitted on April 15, 2004
Accepted on September 28, 2004

17{beta}-Estradiol-Dependent Activation of Signal Transducer and Activator of Transcription1 (STAT1) in Human Fetal Osteoblasts is Dependent on Src Kinase Activity

Angela M. Kennedy, Kristen L. Shogren, Minzhi Zhang, Russell T. Turner, Thomas C. Spelsberg, and Avudaiappan Maran*

Dept. Of Orthopedics and Biochemistry and Molecular Biology, Mayo Foundation, Rochester, MN 55905

* To whom correspondence should be addressed. E-mail: maran{at}mayo.edu.

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 17{beta}-estradiol on the regulation of signal transducer and activator of transcription1 (Stat1) protein in cultured human fetal osteoblast (hFOB) cells, devoid of the classical estrogen receptors (ER). 17{beta}-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, 17{beta}-estradiol increased {gamma}-activated sequence (GAS)-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 17{beta}-estradiol was not inhibited by ER-antagonist ICI 182,780, providing further evidence that it is not dependent on classical ERs. 17{beta}-Estradiol induced rapid (within 15 min) Stat1 phosphorylation and stimulated GAS-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 17{beta}-estradiol-treated osteoblast and breast cancer cells may partially mediate the actions of estrogen on target cells.
Key words: Stat signaling • Interferon • Estrogen • Osteoblast • Breast Cancer • Bone




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