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ToxSci Advance Access published online on June 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg157
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 8, 2003; accepted May 19, 2003
© 2003 Society of Toxicology

Neurotoxicology

p38 Mitogen-Activated Protein Kinase Regulates Bax Translocation in Cyanide-Induced Apoptosis

Y. Shou 1, L. Li 1, K. Prabhakaran 1, J. L. Borowitz 1, and G. E. Isom 1*

1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333

* To whom correspondence should be addressed. E-mail: geisom{at}purdue.edu.


  Abstract

Execution of cyanide-induced apoptosis is mediated by release of cytochrome c from mitochondria. To determine how cyanide initiates cytochrome c release, Bax translocation was investigated in primary cultures of cortical neurons. Under non-apoptotic (control) conditions, Bax resided predominantly in the cytoplasm. After 300 µM cyanide treatment for 1 hr, Bax translocated to the mitochondria as shown by immunocytochemical staining and subcellular fractionation; western blot analysis confirmed "cytosol-to-mitochondria" translocation of Bax. Temporal analysis showed that Bax translocation preceded cytochrome c release from the mitochondria, which was initiated 3 hr after cyanide treatment. In double immunofluorescence labeling for both Bax and cytochrome c, it was observed that cytochrome c was released only in cells showing Bax in mitochondria. The role of p38 mitogen-activated protein (MAP) kinase in Bax translocation was studied. The p38 MAP kinase was activated 30 min after cyanide and its phosphorylation level of activity began to decrease 3 hr later. SB203580, a p38 MAP kinase inhibitor, blocked translocation of Bax to mitochondria while SB202474, a control peptide, had no effect on translocation. Inhibition of p38 MAP kinase by SB203580 blocked all downstream effects of Bax translocation, including cytochrome c release, caspase activation and internucleosomal DNA fragmentation. These results demonstrated that Bax translocation is critical for cyanide-induced cytochrome c release and p38 MAP kinase regulates Bax translocation from cytosol to mitochondria.

Key Words: cyanide, apoptosis, Bax, p38 MAP kinase, cytochrome c .


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