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-α 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. 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-α 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. Synthesized in the sphingolipid pathway from serine and palmitoyl-CoA (1.Merrill Jr, A.H. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway.J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar) or generated by sphingomyelinase activity (2.Hannun Y.A. Obeid L.M. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind.J. Biol. 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Distinct nuclear import and export pathways mediated by members of the karyopherin β family.J. Cell. Biochem. 1998; 70: 231-239Crossref PubMed Scopus (60) Google Scholar, 29.Faustino R.S. Stronger L.N. Richard M.N. Czubryt M.P. Ford D.A. Prociuk M.A. Dibrov E. Pierce G.N. RanGAP-mediated nuclear protein import in vascular smooth muscle cells is augmented by lysophosphatidylcholine.Mol. Pharmacol. 2007; 71: 438-445Crossref PubMed Scopus (18) Google Scholar). Importin-α is returned to the cytosol by CAS (for Cellular Apoptosis Susceptibility), a nuclear export protein specific for the α subunit (30.Behrens P. Brinkmann U. Wellmann A. CSE1L/CAS: its role in proliferation and apoptosis.Apoptosis. 2003; 8: 39-44Crossref PubMed Scopus (99) Google Scholar). Importin-β is recycled independently of the α subunit, and the NLS bearing protein cargo is released into the nuclear interior to modulate gene expression and growth (28.Moroianu J. Distinct nuclear import and export pathways mediated by members of the karyopherin β family.J. Cell. Biochem. 1998; 70: 231-239Crossref PubMed Scopus (60) Google Scholar). Nuclear protein import is one step in a complex series of events that ultimately leads to cell growth. In this study, we investigated the potential for antiproliferative effects of ceramide in VSMCs to be mediated through an action on nuclear protein import. Although overt changes in nucleocytoplasmic trafficking will dramatically affect cellular homeostasis, it is unclear whether subtle stimuli can sufficiently alter transport to effect physiological and pathological changes in cell growth. Although metabolism plays an important role in modifying nuclear protein import (31.Maul G.G. Deaven L.L. Freed J.J. Campbell G.L. Becak W. Investigation of the determinants of nuclear pore number.Cytogenet. Cell Genet. 1980; 26: 175-190Crossref PubMed Scopus (49) Google Scholar), it currently remains unknown whether a lipid metabolite can inhibit nuclear transport. This suggestion was based upon an association of nuclear pore density with cellular transcriptional capacity and “release of products to the cytoplasm” (31.Maul G.G. Deaven L.L. Freed J.J. Campbell G.L. Becak W. Investigation of the determinants of nuclear pore number.Cytogenet. Cell Genet. 1980; 26: 175-190Crossref PubMed Scopus (49) Google Scholar). More recently, it was shown that phosphorylation plays an important regulatory role in nuclear protein import (32.Czubryt M.P. Austria J.A. Pierce G.N. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.J. Cell Biol. 2000; 148: 7-16Crossref PubMed Scopus (61) Google Scholar, 33.Massaeli H. Austria J.A. Pierce G.N. Chronic exposure of smooth muscle cells to minimally oxidized LDL results in depressed inositol 1,4,5-trisphosphate receptor density and Ca(2+) transients.Circ. Res. 1999; 85: 515-523Crossref PubMed Scopus (30) Google Scholar). However, little is known concerning the direct modulatory effects of specific lipid metabolism molecules on nuclear protein import within a cell. This is particularly important in vascular diseases like atherosclerosis and hypertension, in which lipids, cell growth, and cell proliferation play important pathogenic roles. Here, ceramide demonstrates a capacity to induce strong inhibitory effects on nuclear protein import, ultimately reflecting changes in cellular growth and and were from Ceramide was from p38 mitogen-activated protein kinase SB 202190, SB and were from the were from for CAS and importin-α were from and p38 were from Cell proliferating cell nuclear antigen was from and and cyclin were from were from VSMCs were cultured from from R.S. Stronger L.N. Richard M.N. Czubryt M.P. Ford D.A. Prociuk M.A. Dibrov E. Pierce G.N. RanGAP-mediated nuclear protein import in vascular smooth muscle cells is augmented by lysophosphatidylcholine.Mol. Pharmacol. 2007; 71: 438-445Crossref PubMed Scopus (18) Google Scholar, M.P. Austria J.A. Pierce G.N. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.J. Cell Biol. 2000; 148: 7-16Crossref PubMed Scopus (61) Google Scholar, 33.Massaeli H. Austria J.A. Pierce G.N. Chronic exposure of smooth muscle cells to minimally oxidized LDL results in depressed inositol 1,4,5-trisphosphate receptor density and Ca(2+) transients.Circ. Res. 1999; 85: 515-523Crossref PubMed Scopus (30) Google Scholar). were on at of or and for with at in the nuclear import for in were at a density of Cell were by and a Nuclear protein import were (32.Czubryt M.P. Austria J.A. Pierce G.N. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.J. Cell Biol. 2000; 148: 7-16Crossref PubMed Scopus (61) Google Scholar, R. Czubryt M.P. Pierce G.N. The nuclear protein import in vascular smooth muscle Pharmacol. 2000; PubMed Scopus Google Scholar). nuclear import nuclear import and and rat cytosol was with and ceramide to Nuclear import was with ceramide for and to effects of ceramide SB was to the nuclear import in the nuclear import p38 was at a of with or SB and with nuclear import for at in the nuclear import VSMCs for the transport cells were with and with after Nuclear import was initiated by with VSMCs of import of substrate in a and at The in this was to which was to a NLS in the in After import, cells were with for and on a the and the Nuclear was on a and were VSMCs were in a and of and was R.S. M.N. Pierce G.N. of mitogen-activated protein on nuclear protein J. Pharmacol. PubMed Google Scholar). was at in a of substrate in nuclear import ceramide (for a of was to a a that were in the a of that the of the cell an the was into the cell in to the The was with the were and the was from the cell. of the cell were on a for the nuclear import were of and cells by to the of nuclear import for cell and nuclear import were for the nuclear import with these the substrate was not and after cells were with were with and in and for at were with and and on of a of or in a the of cyclin were with a of cyclin were for at and with a of for were with and on After cells were a and a on a were a and and were on a from to with for and Nuclear was by to to the nuclear was for activation a of exposure to a phosphorylation and was to the rat cytosolic at and for the addition of ceramide at the of at was the addition of The was by and the proteins were for p38 was at in Cell were for protein expression with a of and were are by by and was at cell nuclear import was to be one of The nuclear of substrate in VSMCs was with that in after ceramide treatment of import was first after of with and cells significant changes in nuclear Although ceramide was for were investigated for possible effects on nuclear transport. of significant with cells, and effects on nucleocytoplasmic transport in nuclear import been (32.Czubryt M.P. Austria J.A. Pierce G.N. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.J. Cell Biol. 2000; 148: 7-16Crossref PubMed Scopus (61) Google Scholar, R.S. M.N. Pierce G.N. of mitogen-activated protein on nuclear protein J. Pharmacol. PubMed Google Scholar, M.N. D. Pierce G.N. stimulates smooth muscle cell growth, nuclear protein import and nuclear pore expression through mitogen-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). The p38 SB 202190, was with ceramide cytosol to the of p38 Although treatment with SB or effects on nuclear import not nuclear of cells was to supplemented with pharmacological antagonist effects of p38 were by of cells with p38 of nuclear import, by with were to in the of SB the and activation of cytosolic p38 after ceramide which was reversed after with SB cells were with substrate ceramide to nuclear transport cells to with substrate localization in and the after application after nuclear in the of ceramide was inhibited with treatment with transport to upon with SB This was with with ceramide a inhibition of transport Importin-α recognizes the classical NLS in the and is known to between nuclear and cytosolic cells for importin-α cytoplasmic with nuclear localization nuclear envelope However, of VSMCs with ceramide to nuclear of with of strong nuclear and cytoplasmic nuclear was after ceramide treatment with a from nuclear to nuclear CAS is an that importin-α J. P. Bischoff F.R. G. is involved in export of yeast importin α from the Cell. Biol. 1998; PubMed Google Scholar). revealed strong with CAS in cells Ceramide application diminished CAS but nuclear localization was after the addition of SB of CAS the inhibition of localization after ceramide with after SB proliferation after ceramide was investigated by cell by the expression and distribution of markers with or ceramide for and diminished cell results with ceramide are This was reversed upon addition of SB or SB specific of p38 Cellular capacity for growth is by cyclin and nuclear localization of factors cyclin the cell for a of synthesis Prociuk M.A. Austria J.A. G. Pierce G.N. the growth of proliferating cells by nuclear translocation of cell cycle Biol. PubMed Scopus Google Scholar). Here, nuclear of cyclin ceramide treatment cellular distribution of cyclin or is an for cellular proliferation Prociuk M.A. Austria J.A. H. G. Pierce G.N. stimulates cell proliferation through a of cell cycle J. Cell 2003; PubMed Scopus Google Scholar). with ceramide for the expression of and was effectively reversed with the addition of SB Although of the pharmacological SB with SB with cells, of ceramide-induced expression changes revealed a significant to in in nuclear transport direct on cellular and can of cellular growth and the nuclear transport machinery of regulation at but the of lipid in nucleocytoplasmic regulation is not fully address nuclear transport was in VSMCs in the or of Here, ceramide initiated p38 that classical nuclear import in with of cellular proliferation reversed by specific pharmacological This is the first to sphingolipid metabolism to nucleocytoplasmic trafficking with an on cellular growth. Ceramide not affect the import of the NLS not cell to in inhibition of nuclear protein import was the of this effect in Although these data be an of based on that ceramide of nuclear export through a nuclear export signal pathway activity and nuclear export of protein β inhibition of by J. 2002; PubMed Scopus Google Scholar), the in this an NLS and export a nuclear export ceramide not regulate export in this the NLS within the is a sequence that does not an export the effects are to changes in import to export Nuclear import was not to a an action is ceramide can M. The Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) in M. Ceramide the of the to Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), to in the are the required to that the inhibitory capacity of ceramide was the of specific Furthermore, these effects were not to of of ceramide not the potent inhibitory effects treatment of cytosol with in cell nuclear transport and ceramide of is to be a whereby stimulates cellular growth but ceramide inhibits cell growth and apoptosis T. and of Res. 2003; PubMed Scopus Google Scholar, S. S. and Lett. 2000; PubMed Scopus Google Scholar, S. S. a cell Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). This of nuclear import by is not has a inhibition of nuclear protein import by (32.Czubryt M.P. Austria J.A. Pierce G.N. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.J. Cell Biol. 2000; 148: 7-16Crossref PubMed Scopus (61) Google Scholar), a for action CAS was a potential for the effects is a protein U. Brinkmann E. M. 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