Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers

被引:158
作者
Felty, Q
Xiong, WC
Sun, DM
Sarkar, S
Singh, KP
Parkash, J
Roy, D
机构
[1] Robert Stempel Sch Publ Hlth, Chair Environm & Occupat Hlth, Miami, FL 33199 USA
[2] Univ Alabama Birmingham, Dept Environm Hlth Sci, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Mol & Cellular Pathol, Birmingham, AL 35294 USA
[4] Marshall Univ, Sch Med, Dept Anat Cell & Neurobiol, Huntington, WV 25704 USA
关键词
D O I
10.1021/bi047629p
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report here evidence in support of the role of 17 beta-estradiol-(E2-) induced mitochondrial (mt) reactive oxygen species (ROS) as signal-transducing messengers. On the basis of monitoring the oxidation of 2',7'-dichlorofluorescin by spectrofluorometry, flow cytometry, and confocal microscopy, we have identified that exposure of E2 triggers the immediate rapid production of intracellular ROS ranging from a 1- to severalfold increase in a variety of cells. E2-stimulated ROS production does not correlate with the activity of the estrogen receptor (ER) in the cells. The ROS is most likely hydrogen peroxide based on its inhibition by antioxidants and catalase and lack of any effects of E2 on 02(.-) or NO. formation. Confocal microscopy showed that ROS is localized in the perinuclear mitochondria. E2 through anchorage and integrin-dependent signaling to mitochondria increased ROS generation. Increased intracellular ROS formation identified here for the first time may explain the mechanism of previously reported oxidative damage and subsequent genetic alterations including mutations produced by elevated concentrations of estrogens. The functional consequences of E2-induced ROS formation included the enhanced cell motility as shown by the increase in cdc42 and activation of Pyk2 and the increased phosphorylation of signaling proteins c-jun and CREB. E2-induced. ROS activated the binding of three oxidant-sensitive transcription factors: AP-1, CREB, and nuclear respiratory factor 1. In addition to ERs as signaling molecules, our findings further revealed that E2-induced mt ROS also act as signal transducing messengers and suggest new targets for the development of antioxidant-based drugs or antioxidant gene therapy for the prevention and treatment of estrogen-dependent cancer.
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页码:6900 / 6909
页数:10
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