Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 6 July 2004
Vol. 2004, Issue 240, p. tw242
[DOI: 10.1126/stke.2402004TW242]

EDITORS' CHOICE

Apoptosis Estrogen Gets BAD

The steroid hormone estrogen has both pro- and antiapoptotic effects, depending on the cell type. In mammary tissue and breast cancer cell lines, the effect of estrogen 17-β-estradiol (E2) in promoting cell survival has been attributed in part to regulating the expression of anti- and proapoptotic proteins Bcl-2 and Bak, respectively. Fernando and Wimalasena now report a nongenomic pathway by which E2 blocks apoptosis in breast cancer (MCF7) cells. E2 treatment reduced cell death in MCF7 cells that were exposed to proapoptotic stimuli including tumor necrosis factor-alpha (TNF-α). This protective effect of E2 required the rapid phosphorylation and inactivation of BAD, a proapoptotic protein that forms a complex with Bcl-2 to destroy mitochondria integrity. BAD expression was not altered, which indicates that a nongenomic pathway is activated by E2. When MCF7 cells were treated with TNF-α, phosphorylation of BAD on two serine residues decreased. However, E2 treatment both restored BAD phosphorylation and inhibited the cell death response to TNF-α, which indicates a key role for BAD in apoptosis in this cellular context. Expression of a mutant form of BAD lacking the critical serine residues, or expression of antisense oligonucleotides to block the expression of endogenous BAD, reduced the apoptotic response to TNF-α. Expression of a dominant-negative form of Ras blocked E2-mediated phosphorylation of BAD, which suggests that E2 acts through a Ras-dependent mechanism to affect BAD and cell survival. Pharmacologic inhibitors of either the phosphatidylinositol 3-kinase (PI3K)-Akt or the extracellular signal-regulated protein kinase (ERK)-Rsk1 signaling cascades indicated that BAD inactivation, in response to E2, involved both Ras-controlled signaling pathways. The authors propose that the steroid hormone acts through both nongenomic signaling pathways as a mechanism to ensure cell survival when apoptotic stimuli are present simultaneously with estrogen.

R. I. Fernando, J. Wimalasena, Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Mol. Biol. Cell 15, 3266-3284 (2004). [Abstract] [Full Text]

Citation: Estrogen Gets BAD. Sci. STKE 2004, tw242 (2004).


To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882