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

Quentin Felty, Wencheng Xiong, Dongmei Sun, Shubhashish Sarkar, Kamaleshwar P. Singh, Jai Parkash, Deodutta Roy

Research output: Contribution to journalArticle

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Abstract

We report here evidence in support of the role of 17β-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 O 2 •- 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.

Original languageEnglish (US)
Pages (from-to)6900-6909
Number of pages10
JournalBiochemistry
Volume44
Issue number18
DOIs
StatePublished - May 10 2005

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Reactive Oxygen Species
Estrogens
Mitochondria
Antioxidants
Confocal microscopy
Confocal Microscopy
Nuclear Respiratory Factor 1
Proto-Oncogene Proteins c-jun
Gene therapy
Phosphorylation
Flow cytometry
Fluorescence Spectrometry
Transcription Factor AP-1
Oxidants
Integrins
Estrogen Receptors
Genetic Therapy
Catalase
Hydrogen Peroxide
Cell Movement

ASJC Scopus subject areas

  • Biochemistry

Cite this

Felty, Q., Xiong, W., Sun, D., Sarkar, S., Singh, K. P., Parkash, J., & Roy, D. (2005). Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. Biochemistry, 44(18), 6900-6909. https://doi.org/10.1021/bi047629p

Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. / Felty, Quentin; Xiong, Wencheng; Sun, Dongmei; Sarkar, Shubhashish; Singh, Kamaleshwar P.; Parkash, Jai; Roy, Deodutta.

In: Biochemistry, Vol. 44, No. 18, 10.05.2005, p. 6900-6909.

Research output: Contribution to journalArticle

Felty, Q, Xiong, W, Sun, D, Sarkar, S, Singh, KP, Parkash, J & Roy, D 2005, 'Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers', Biochemistry, vol. 44, no. 18, pp. 6900-6909. https://doi.org/10.1021/bi047629p
Felty Q, Xiong W, Sun D, Sarkar S, Singh KP, Parkash J et al. Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. Biochemistry. 2005 May 10;44(18):6900-6909. https://doi.org/10.1021/bi047629p
Felty, Quentin ; Xiong, Wencheng ; Sun, Dongmei ; Sarkar, Shubhashish ; Singh, Kamaleshwar P. ; Parkash, Jai ; Roy, Deodutta. / Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. In: Biochemistry. 2005 ; Vol. 44, No. 18. pp. 6900-6909.
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