Submitted on October 12, 2007
Revised on December 11, 2007
Accepted on December 13, 2007
Ceramide regulation of nuclear protein import
Randolph S. Faustino, Paul Cheung, Melanie N. Richard, Elena Dibrov, Annette L. Kneesh, Justin F. Deniset, Mirna N. Chahine, Kaitlin Lee, David Blackwood, and Grant N. Pierce
Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, Winnipeg, Manitoba R2H 2A6
Corresponding Author: gpierce{at}sbrc.ca
Nucleocytoplasmic trafficking is an essential and responsive cellular mechanism that directly impacts cell growth and proliferation, and its potential to address metabolic challenge is incompletely defined. Ceramide is an anti-proliferative 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 activation of cytosolic p38 MAP kinase. Following application of SB202190, 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-a and CAS, revealed ceramide-mediated relocalization that was reversed upon addition of SB202190. Furthermore, cell counts, nuclear cyclin A, and PCNA expression, markers of cellular proliferation, were diminished after ceramide treatment and effectively rescued by addition of inhibitor. Together these data demonstrate, for the first time, sphingolipid regulation of nuclear import that defines and expands adaptive capacity of the nucleocytoplasmic transport machinery.
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