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Originally published In Press as doi:10.1194/jlr.M700464-JLR200 on December 14, 2007

Papers In Press, published online ahead of print March 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700464-JLR200
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Journal of Lipid Research, Vol. 49, 654-662, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Ceramide regulation of nuclear protein importboxs

Randolph S. Faustino, Paul Cheung, Melanie N. Richard, Elena Dibrov, Annette L. Kneesch, Justin F. Deniset, Mirna N. Chahine, Kaitlin Lee, David Blackwood and Grant N. Pierce1

Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology, Faculties of Medicine and Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.

Published, JLR Papers in Press, December 14, 2007.

1 To whom correspondence should be addressed. e-mail: gpierce{at}sbrc.ca

Nucleocytoplasmic trafficking is an essential and responsive cellular mechanism that directly affects cell growth and proliferation, and its potential to address metabolic challenge is incompletely defined. Ceramide is an antiproliferative sphingolipid found within vascular smooth muscle cells in atherosclerotic plaques, but its mechanism of action remains unclear. The hypothesis that ceramide inhibits cell growth through nuclear transport regulation was tested. In smooth muscle cells, exogenously supplemented ceramide inhibited classical nuclear protein import that involved the activation of cytosolic p38 mitogen-activated protein kinase (MAPK). After application of SB 202190, a specific and potent pharmacological antagonist of p38 MAPK, sphingolipid impingement on nuclear transport was corrected. Distribution pattern assessments of two essential nuclear transport proteins, importin-{alpha} and Cellular Apoptosis Susceptibility, revealed ceramide-mediated relocalization that was reversed upon the addition of SB 202190. Furthermore, cell counts, nuclear cyclin A, and proliferating cell nuclear antigen expression, markers of cellular proliferation, were diminished after ceramide treatment and effectively rescued by the addition of inhibitor. Together, these data demonstrate, for the first time, the sphingolipid regulation of nuclear import that defines and expands the adaptive capacity of the nucleocytoplasmic transport machinery.

Supplementary key words nuclear transport • lipid • mitogen-activated protein kinase






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