Ceramide regulation of nuclear protein import.
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.
Faustino
Randolph S
RS
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology, Faculties of Medicine and Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
Cheung
Paul
P
Richard
Melanie N
MN
Dibrov
Elena
E
Kneesch
Annette L
AL
Deniset
Justin F
JF
Chahine
Mirna N
MN
Lee
Kaitlin
K
Blackwood
David
D
Pierce
Grant N
GN
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001011:Aorta; D049109:Cell Proliferation; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism; D002518:Ceramides / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D028884:Karyopherins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011817:Rabbits; D013107:Sphingolipids / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D029563:Cellular Apoptosis Susceptibility Protein; D002518:Ceramides; D004791:Enzyme Inhibitors; D028884:Karyopherins; D013107:Sphingolipids; D048051:p38 Mitogen-Activated Protein Kinases