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J. Biol. Chem., Vol. 279, Issue 45, 46748-46754, November 5, 2004
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B*
¶
From the
Musculo-Skeletal Research Unit and the Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York 14642
Treatment of various types of cells with the mitochondrial ATP-sensitive K+ channel opener, diazoxide, preconditions cells to subsequent injuries and inhibits apoptosis. The mechanism of such preconditioning is not well understood. We have studied the effect of diazoxide pretreatment on mitochondrial morphology and function in HL60 cells and on susceptibility of these cells to apoptosis. We have found that diazoxide pretreatment inhibited etoposide-induced apoptosis and mitochondrial dysfunction. Diazoxide induced moderate mitochondrial swelling and increase in the cytosolic fraction of mitochondrial intermembrane proteins including cytochrome c without any significant effect on the oxidative phosphorylation function or membrane potential. Possibly as an adaptive response, total protein and mRNA levels of cytochrome c and of the anti-apoptotic Bcl-2 family member, Bcl-xl, increased. These effects coincided with activation of the transcription factors cAMP-response element-binding protein (CREB) and NF
B. The gene encoding cytochrome c carries the cAMP-response element (CRE), and the gene encoding Bcl-xl carries both the CRE and NFB response elements. The inability of etoposide to trigger apoptosis in preconditioned cells was most likely because of prosurvival signaling by CREB and NFB, which included up-regulation of cytochrome c and Bcl-xl. All described effects were reversed by a specific mitochondrial ATP-sensitive K+ channel inhibitor, 5-hydroxydecanoate, proving the specificity of the action of diazoxide. Preconditioning was also reversed by a specific NFB inhibitor, SN50, proving the importance of this transcription factor for the phenomenon of preconditioning. CREB and NFB were activated most likely in response to an observed elevation in cytosolic calcium following diazoxide treatment. We, therefore, conclude that diazoxide-mediated preconditioning against apoptosis involves activation of the pro-survival transcription factors CREB and NFB.
Received for publication, June 3, 2004 , and in revised form, August 19, 2004.
* This work was supported by National Institutes of Health Grant RO1 ES10041. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of Rochester School of Medicine, Box 712, 575 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-3129; Fax: 585-275-6007; E-mail: Thomas_Gunter{at}urmc.rochester.edu.
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