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J. Biol. Chem., Vol. 278, Issue 48, 47498-47507, November 28, 2003

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Mitochondrial Cytochrome c Release Mediates Ceramide-induced Activator Protein 2 Activation and Gene Expression in Keratinocytes^*

Susanne Grether-Beck, Ingo Felsner, Heidi Brenden, and Jean Krutmann

From the Cell Biology, Institut fuer Umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University gGmbH, Auf'm Hennekamp 50, D-40225 Duesseldorf, Germany

The intracellular signaling pathway(s) through which second messenger ceramides induce gene expression in human cells has not yet been characterized. In the present study, ceramide-induced expression of intercellular adhesion molecule-1 (ICAM-1), which requires activation of transcription factor activator protein 2 (AP-2), was found to be mediated through a mitochondrial pathway. Inhibitors of mitochondrial electron transport chain (e.g. rotenone, thenoyltrifluoroacetone, and antimycin A) reduced ceramide-induced ICAM-1 expression. Stimulation of human keratinocytes with cell-permeant ceramides at concentrations that did not induce apoptosis (no activation of caspases 3, 8, and 9 and no nucleosomal fragmentation) but caused AP-2 activation and ICAM-1 induction released cytochrome c (cyt c) from mitochondria into the cytoplasm of cells. This cyt c release was an indispensable prerequisite for effective ceramide signaling, because its inhibition by modulating the mitochondrial megachannel with bonkrekic acid or carboxyatractyloside prevented ceramide-induced AP-2 activation and ICAM-1 expression. Analysis of the interaction between cyt c and AP-2 revealed that cyt c oxidized AP-2 and that this redox regulation greatly enhanced the DNA binding capacity of AP-2. Mitochondria thus have a previously unrecognized function in signaling ceramide-induced transcription factor activation and gene regulation.

Received for publication, August 27, 2003

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 503, project B2, and Louis Vuitton Moet Hennessy (Paris, France). 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.

This paper is dedicated to Professor Lothar Jaenicke, Institute of Biochemistry at the University of Cologne, Germany, on the occasion of his 80th birthday in September 2003, in recognition of his important contributions to biochemistry.

To whom correspondence should be addressed: Institut fuer Umweltmedizinische Forschung at the Heinrich-Heine-University gGmbH, Auf'm Hennekamp 50, 40225 Duesseldorf, Germany. Tel.: 49-211-3389-224; Fax: 49-211-3389-226; E-mail: krutmann{at}rz.uni-duesseldorf.de.

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