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Papers In Press, published online ahead of print November 1, 2000
Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642
Corresponding Author: Robert_Freeman{at}urmc.rochester.edu
Sympathetic neurons undergo protein synthesis-dependent apoptosis when deprived of nerve growth factor (NGF). Expression of SM-20 is upregulated in NGF-deprived sympathetic neurons and ectopic SM-20 is sufficient to promote neuronal death in the presence of NGF. We now report that SM-20 is a mitochondrial protein that promotes cell death through a caspase-dependent mechanism. SM-20 immunofluorescence was present in the cytoplasm in a punctate pattern that co-localized with cytochrome oxidase I and with mitochondria-selective dyes. Analysis of SM-20/dihydrofolate reductase fusion proteins revealed that the first 25 amino acids of SM-20 contain a functional mitochondrial targeting sequence. An amino-terminal truncated form of SM-20 was not restricted to mitochondria but instead localized throughout the cytosol and nucleus. Nevertheless, the truncated SM-20 retained the ability to induce neuronal death, similar to the wild type protein. SM-20 induced death was accompanied by caspase-3 activation and was blocked by a general caspase inhibitor. Additionally, overexpression of SM-20, under conditions where cell death is blocked by a general caspase inhibitor, did not result in widespread release of cytochrome c from mitochondria. These results indicate that SM-20 is a novel mitochondrial protein that may be an important mediator of neurotrophin-withdrawal mediated cell death.
J. Biol. Chem, 10.1074/jbc.M008407200
Submitted on September 13, 2000
Revised on October 27, 2000
Accepted on November 1, 2000
SM-20: a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons
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