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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/E589    most recent 00705.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Flynn, J. M. Articles by Cammarata, P. R. PubMed PubMed Citation Articles by Flynn, J. M. Articles by Cammarata, P. R.

RNA suppression of ERK2 leads to collapse of mitochondrial membrane potential with acute oxidative stress in human lens epithelial cells

¹Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas; and ²Center for Cell Signaling and the Department of Microbiology, University of Virginia, School of Medicine, Charlottesville, Virginia

Submitted 1 November 2007 ; accepted in final form 28 December 2007

17β-Estradiol (E₂) reduces oxidative stress-induced depolarization of mitochondrial membrane potential (MMP) in cultured human lens epithelial cells (HLE-B3). The mechanism by which the nongenomic effects of E₂ contributed to the protection against mitochondrial membrane depolarization was investigated. Mitochondrial membrane integrity is regulated by phosphorylation of BAD, and it is known that phosphorylation of Ser¹¹² inactivates BAD and prevents its participation in the mitochondrial death pathway. We found that E₂ rapidly increased both the phosphorylation of ERK2 and Ser¹¹² in BAD. Ser¹¹² is phosphorylated by p90 ribosomal S6 kinase (RSK), a Ser/Thr kinase, which is a downstream effector of ERK1/2. Inhibition of RSK by the RSK-specific inhibitor SL0101 did not reduce the level of E₂-induced phosphorylation of Ser¹¹². Silencing BAD using small interfering RNA did not alter mitochondrial membrane depolarization elicited by peroxide insult. However, under the same conditions, silencing ERK2 dramatically increased membrane depolarization compared with the control small interfering RNA. Therefore, ERK2, functioning through a BAD-independent mechanism regulates MMP in humans lens epithelial cells. We propose that estrogen-induced activation of ERK2 acts to protect cells from acute oxidative stress. Moreover, despite the fact that ERK2 plays a regulatory role in mitochondrial membrane potential, estrogen was found to block mitochondrial membrane depolarization via an ERK-independent mechanism.

17β-estradiol; mitochondrial membrane potential; mitochondrial permeability transition