Phosphatidylinositol transfer protein α regulates growth and apoptosis of NIH3T3 cells

Abstract

Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein α [PI-TPα; sense PI-TPα (SPIα) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-α-induced apoptosis. The conditioned medium (CM) from SPIα cells or the neutral lipid extract from CM stimulated the proliferation of quiescent wild-type NIH3T3 cells. CM was also highly effective in increasing resistance toward induced apoptosis in both wild-type cells and the highly apoptosis-sensitive SPIβ cells (i.e., wild-type cells overexpressing PI-TPβ). CM from SPIα cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity. This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. In accordance, SPIα cells express enhanced levels of COX-1 and COX-2. The antiapoptotic activity of CM from SPIα cells tested on SPIβ cells was inhibited by ∼50% by pertussis toxin and suramin as well as by SR141716A, a specific antagonist of the cannabinoid 1 receptor. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPIα cells..The latter results imply that PI-TPα mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor. Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein α [PI-TPα; sense PI-TPα (SPIα) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor-α-induced apoptosis. The conditioned medium (CM) from SPIα cells or the neutral lipid extract from CM stimulated the proliferation of quiescent wild-type NIH3T3 cells. CM was also highly effective in increasing resistance toward induced apoptosis in both wild-type cells and the highly apoptosis-sensitive SPIβ cells (i.e., wild-type cells overexpressing PI-TPβ). CM from SPIα cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity. This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. In accordance, SPIα cells express enhanced levels of COX-1 and COX-2. The antiapoptotic activity of CM from SPIα cells tested on SPIβ cells was inhibited by ∼50% by pertussis toxin and suramin as well as by SR141716A, a specific antagonist of the cannabinoid 1 receptor. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPIα cells.. The latter results imply that PI-TPα mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor. Phosphatidylinositol transfer proteins (PI-TPs) belong to a family of highly conserved proteins that in vitro can catalyze the transfer of phosphatidylinositol, phosphatidylcholine, and sphingomyelin between membranes (1Wirtz K.W. Phospholipid transfer proteins revisited.Biochem. J. 1997; 324: 353-360Crossref PubMed Scopus (174) Google Scholar, 2Li H. Tremblay J.M. Yarbrough L.R. Helmkamp Jr., G.M. Both isoforms of mammalian phosphatidylinositol transfer protein are capable of binding and transporting sphingomyelin.Biochim. Biophys. Acta. 2002; 1580: 67-76Crossref PubMed Scopus (19) Google Scholar). In mammalian tissues, at least two isoforms are identified: PI-TPα, which is localized in the nucleus and cytosol, and PI-TPβ, which is associated with the Golgi system (3De Vries K.J. Westerman J. Bastiaens P.I. Jovin T.M. Wirtz K.W. Snoek G.T. Fluorescently labeled phosphatidylinositol transfer protein isoforms (alpha and beta), microinjected into fetal bovine heart endothelial cells, are targeted to distinct intracellular sites.Exp. Cell Res. 1996; 227: 33-39Crossref PubMed Scopus (81) Google Scholar). Possible cellular functions of these proteins have been obtained from experiments with permeabilized cells (4Cockcroft S. Reconstitution system based on cytosol-depleted cells to study the regulation of phospholipases C and D.Methods Mol. Biol. 1998; 84: 185-197PubMed Google Scholar), reconstituted Golgi membrane systems (5Ohashi M. Jan de Vries K. Frank R. Snoek G. Bankaitis V. Wirtz K. Huttner W.B. A role for phosphatidylinositol transfer protein in secretory vesicle formation.Nature. 1995; 377: 544-547Crossref PubMed Scopus (169) Google Scholar), and cells in which the expression of the proteins has been altered (6Monaco M.E. Alexander R.J. Snoek G.T. Moldover N.H. 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On the other hand, intact mouse fibroblast cells with increased expression of PI-TPα [sense PI-TPα (SPIα) cells] showed an enhanced phospholipase A2 (PLA2)-mediated degradation of PI that was not observed in cells with an increased expression of PI-TPβ (SPIβ cells) (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 8Van Tiel C.M. Luberto C. Snoek G.T. Hannun Y.A. Wirtz K.W. Rapid replenishment of sphingomyelin in the plasma membrane upon degradation by sphingomyelinase in NIH3T3 cells overexpressing the phosphatidylinositol transfer protein beta.Biochem. J. 2000; 346: 537-543Crossref PubMed Scopus (31) Google Scholar). Convincing evidence for distinct cellular functions was obtained by genetic approaches. Murine embryonic stem cells deficient in PI-TPβ fail to develop, whereas the embryonic development of cells deficient in PI-TPα proceeds normally (12Alb Jr., J.G. Phillips S.E. Rostand K. Cui X. Pinxteren J. Cotlin L. Manning T. Guo S. York J.D. Sontheimer H. Collawn J.F. Bankaitis V.A. Genetic ablation of phosphatidylinositol transfer protein function in murine embryonic stem cells.Mol. Biol. Cell. 2002; 13: 739-754Crossref PubMed Scopus (60) Google Scholar, 13Alb Jr., J.G. Cortese J.D. Phillips S.E. Albin R.L. Nagy T.R. Hamilton B.A. Bankaitis V.A. Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia.J. Biol. Chem. 2003; 278: 33501-33518Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). In the latter case, the mice die within 2 weeks of birth. The rate of proliferation of SPIα cells is significantly increased, with a cell cycle duration of 13 h compared with 21 h for wild-type cells, indicating that PI-TPα may be involved in the production of a mitogenic factor (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). The observation that in SPIα cells a PI-specific PLA2 is activated implies that, in addition to lysoPI, a significant amount of arachidonic acid is produced because PI is highly enriched in this fatty acid (14Alonso F. Henson P.M. Leslie C.C. A cytosolic phospholipase in human neutrophils that hydrolyzes arachidonoyl-containing phosphatidylcholine.Biochim. Biophys. Acta. 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The is the conditioned medium quiescent cells with CM that was from an of cells (i.e., well of a was with the amount of CM that was conditioned for h by of cells in and with in a at NIH3T3 mouse fibroblast cells overexpressing PI-TPα cells) and PI-TPβ (SPIβ cells) as (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 8Van Tiel C.M. Luberto C. Snoek G.T. Hannun Y.A. Wirtz K.W. Rapid replenishment of sphingomyelin in the plasma membrane upon degradation by sphingomyelinase in NIH3T3 cells overexpressing the phosphatidylinositol transfer protein beta.Biochem. J. 2000; 346: 537-543Crossref PubMed Scopus (31) Google Scholar). In this have two SPIα cell and cells on the medium was by 1 of the medium was by of CM or of with of the The of medium that had been conditioned by 2 of cells was to well of a in of was to the cells. h the medium was the cells with and 1 of well was The was and the cells to on A of of was and the cells for at and The cells with of and cells with of was obtained by the addition of cells grown on a or the cells for h in of the that tested for activity to this the The medium was and was in a with the with pertussis toxin in by of pertussis toxin in CM from SPIα cells for suramin and the cannabinoid 1 and 2 and for h in CM from SPIα cells. with of was and cells at the cell was as the of cells that are in the of which have a for of the cells grown on and The cells in and with 1 in for at with and with and in with with a grown in to as with CM for was and of was to the at 2 the medium was and with 1 of This was with the medium and to cells. Cell with 1 of in for and for at at Both cell and in of with and on for A of of in was on of the The was and at and to as a of apoptosis with is by and X. of apoptosis and by of with of Cell Res. 1996; PubMed Scopus Google the cell was for at at The was and the was in 1 of and for at The was in 1 of a of and The was for at by at the was in 1 of and and the was in the for at least the was a cell to and other of the and was on a with a at The of was in in is that an nucleus into one in the the be This a of cells compared with as are at an at 2 h grown in 21 to with and CM was the cells, the medium was cells with and the the cells with of in for at and on The cell was for at at and the was to protein the A and for the of of protein the of PubMed Scopus Google Scholar). of protein of for A of of protein was to on a and by COX-1 and of on was by with a with an grown to The cells labeled for h with acid well on a in 1 of labeled arachidonic acid in the medium was h and by this medium was and to cells. acid in the CM and as by and of in of J. PubMed Scopus Google Scholar). of acid was of The was with two of The The was in and on a The was in the of as the was by the with a had that SPIα cells have a cell cycle duration of 13 h compared with 21 h for wild-type NIH3T3 cells (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). In of this highly increased rate of CM from SPIα cells tested for the production of a mitogenic factor by the of into of cells. in the CM from SPIα cells increased synthesis by a factor of CM from cells increased the synthesis by a factor of This that SPIα cells a mitogenic factor that is into the the enhanced degradation of PI in SPIα cells as in the levels of and inositol (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), is most that arachidonic acid also is which can be by and into to be into the medium An S. of expression and of eicosanoid in and human J. 1995; PubMed Scopus Google Scholar). and other from a neutral of in of J. PubMed Scopus Google Scholar). in the lipid extract of CM from SPIα cells increased synthesis in quiescent cells by whereas the of CM from had a that the mitogenic activity in the neutral lipid is enhanced to that of the medium was conditioned in the presence of a of COX-1 and the CM was no mitogenic for quiescent cells In the presence of NS398, a of the CM a of mitogenic indicating that the mitogenic factor(s) is on activity not The of the lipid extract was not not indicating that mitogenic activity was in the the neutral lipid extract from the cell was indicating that mitogenic activity was in the the rate of proliferation is with apoptosis M. cell proteins in Cell Res. 1999; PubMed Scopus Google Scholar, D. The of 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), compared the of the and SPIα cells upon apoptosis was by the of cells at 2 h the cells to of a from to the SPIα cells toward compared with cells to as a function of upon a of that SPIα cells are highly toward apoptosis the the apoptosis of cells overexpressing PI-TPβ was also with the cells, the SPIβ cells to be toward apoptosis. This that SPIα cells have a resistance of and SPIα cells upon of apoptosis by grown to The medium was by and the cells for h at of the cells as was to the cells, and the of cells was at the of cells in and SPIα cell at 2 h increasing of of apoptosis in and SPIα cell with cells with with CM from SPIα cells, and with the neutral lipid extract and CM from SPIα cells cell with and was of cells at and SPIβ cells with with with CM from SPIα cells, or with CM from SPIα cells in the presence of the cell with and was of cells at and of at least that cell also antiapoptotic activity J. E. M. endothelial factor endothelial cell and tumor J. 2002; PubMed Scopus Google Scholar, A.J. van P.M. The cell and of protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the between the mitogenic factor and apoptosis CM from SPIα cells is to cells apoptosis. for h with CM from SPIα cells, the cells was observed the wild-type cells with the neutral lipid extract of CM from SPIα cells. The CM from SPIα cells is also effective in the highly SPIβ cells Tiel C.M. M. Snoek G.T. Wirtz Overexpression of phosphatidylinositol transfer protein in NIH3T3 cells has a effect on sphingomyelin synthesis and Biophys. Acta. PubMed Scopus Google apoptosis that inhibited the mitogenic activity of CM from SPIα cells also the effect of on the antiapoptotic activity. in CM in the presence of was effective in SPIβ cells apoptosis. is that the effect of on the mitogenic activity of CM from SPIα cells is effect on the antiapoptotic activity and This suggests that the factor cell at a cell or that the SPIα cells an antiapoptotic factor of In addition to cells, the of cells by by of that labeled with at 2 h that the of apoptosis increased in the SPIα SPIβ cells for h with CM from SPIα cells the of was significantly the antiapoptotic activity of the SPIα This effect was SPIα medium in the presence of The of NIH3T3 and SPIα cells toward apoptosis was by of the of and SPIα cells was intact by for h with the of cells showed whereas the of SPIα cells This that in the of cells, by is an the of the cells showed a significant in whereas the effect on the of SPIα cells was and the production of the mitogenic indicating that the bioactive factor in CM from SPIα cells is an arachidonic acid CM from SPIα cells labeled for h with the medium with and the lipid extract by in acid in CM from SPIα cells whereas the of in CM from cells with arachidonic acid of CM from SPIα cells in the presence of a specific inhibitor, or of not showed that of the be that and with two of the arachidonic an was that SPIα cells produced compared with and was that both or to the of quiescent cells in the in CM from SPIα cells. results obtained by and not indicating that the COX-2-dependent mitogenic factor be an as the production of a mitogenic factor(s) by SPIα cells, the expression of COX-1 and in these cells by In SPIα cells, COX-1 and are increased and compared with cells In with CM from SPIα cells for h to a of in cells and a in SPIβ cells, in with the increased resistance of these cells toward apoptosis these CM from SPIα cells has effect on the of of the antiapoptotic activity in CM from SPIα cells, inhibitors of G-protein-coupled of SPIβ cells with CM from SPIα cells in the presence of suramin or pertussis toxin inhibited the antiapoptotic effect by A specific of the has been to in by of a the cannabinoid 1 der M. W.B. van F. T. J.F. V. K. in PubMed Google Scholar, der M. W.B. J.F. K. by the in in PubMed Google Scholar). PI-TPα to an role in B.A. van V. L. The expression of and 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), was a between the of SPIβ cells by CM from SPIα cells and the and with the antagonist for h the antiapoptotic activity of CM from SPIα cells by these the antagonist to have no On the other hand, in to pertussis and SR141716A, which had no effect on the apoptosis of the SPIβ cells (i.e., the antagonist showed a distinct antiapoptotic activity the that the antiapoptotic factor also the of the receptor. addition of pertussis or to CM from SPIα cells in the presence of NS398, a specific inhibitor, to in a significant of antiapoptotic activity not These results strongly that at least one of the antiapoptotic produced by SPIα cells is a COX-2-dependent the of a receptor. In this show that NIH3T3 cells overexpressing PI-TPα cells) are toward apoptosis compared with cells. CM from SPIα cells was to or SPIβ cells, which are to these cells also apoptosis In CM from SPIα cells as well as the neutral lipid extract from CM the of quiescent cells. and mitogenic activity in the CM was significantly diminished the SPIα cells with inhibitors of the In with on SPIα cells enriched in (7Snoek G.T. Berrie C.P. Geijtenbeek T.B. van der Helm H.A. Cadee J.A. Iurisci C. Corda D. Wirtz K.W. Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells activates a phospholipase A.J. Biol. Chem. 1999; 274: 35393-35399Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), CM from SPIα cells is highly enriched in arachidonic acid compared with for This the of PLA2 by PI-TPα, in the degradation of PI into and arachidonic which is into and in the presence of the NS398, arachidonic acid from CM of SPIα cells, that these a of the mitogenic and antiapoptotic activity PI-TPα is localized in the and in the nucleus (3De Vries K.J. Westerman J. Bastiaens P.I. Jovin T.M. Wirtz K.W. Snoek G.T. Fluorescently labeled phosphatidylinositol transfer protein isoforms (alpha and beta), microinjected into fetal bovine heart endothelial cells, are targeted to distinct intracellular sites.Exp. Cell Res. 1996; 227: 33-39Crossref PubMed Scopus (81) Google Scholar, G.T. de van Wirtz K.W. The phosphatidylinositol transfer protein in mouse fibroblast cells is associated with the Golgi Cell. PubMed Scopus Google Scholar). The of the is not the presence of an PI in the nucleus is well L. L. and PubMed Scopus Google Scholar). of mammalian cells have been to an cycle PLA2 activity in G. signaling in the system and other Res. Full Text Full Text PDF PubMed Scopus Google because mammalian also a significant of M.E. The and of in cellular J. 1998; PubMed Scopus Google Scholar), to be the production of and arachidonic acid in the In cell is the COX-2-dependent to cell in an and of cyclooxygenase-2 in cellular and in Cell. 2002; PubMed Scopus Google Scholar). The mitogenic of are by the of and PubMed Scopus Google Scholar). or with was tested on quiescent cells, to the and enhanced to the of these cells On the other hand, of SPIβ cells with these had no effect on the of the SPIβ cells, which not This strongly suggests that SPIα cells COX-2-dependent mitogenic from or the of which to be that these are also in cells induced apoptosis. is well that the of apoptosis by antiapoptotic as well as by the arachidonic acid of cyclooxygenase-2 in cellular and in Cell. 2002; PubMed Scopus Google Scholar, H. J. J.D. of apoptosis and expression by in human Res. 1998; Google Scholar, L. D. V. F. acid cell the for tumor necrosis Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the of the SPIα cells, the arachidonic acid by PI-TPα from PI is by the of which is highly increased compared with and SPIβ cells of the SPIβ cells with CM from SPIα cells increased the of not of This and SPIβ cells are apoptosis by CM from SPIα cells. On the other hand, CM from SPIα cells in the presence of the showed antiapoptotic activity This that the factor cell at a cell proliferation or that, in addition to SPIα cells also antiapoptotic into the of the factor was by the effect of both inhibitors and the and on the antiapoptotic activity of CM from SPIα cells M. F. M. D. C. S. J. G. D. J. G. SR141716A, a and antagonist of the cannabinoid PubMed Scopus Google Scholar, D. The of 2003; PubMed Scopus Google Scholar). The in antiapoptotic activity induced by pertussis and the specific antagonist strongly suggests that the antiapoptotic factor produced by SPIα cells is an which of the CM from SPIα cells in the or presence of inhibitors or in with the inhibitors showed antiapoptotic activity (i.e., of the This that the of the is to the COX-2-dependent cannabinoid M. A. The and the regulation of mammalian cell 2003; PubMed Scopus Google Scholar, L. V. The a and J. PubMed Scopus Google Scholar). 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Chem. 2003; 278: 33501-33518Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). mice to and are that PI-TPα is not for embryonic these mice to other increased apoptosis the The of PI-TPα for function is also from the which has to PI-TPα levels in the B.A. van V. L. The expression of and 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). that transfer activity is in and from as a of levels of PI-TPα J. Westerman J. F. Phospholipid proteins in and from PubMed Scopus Google Scholar), the cells of mice may be well apoptosis by PI-TPα the synthesis of the antiapoptotic this be to the of mice can be by the in or of the eicosanoid factor produced by SPIα cells. The for the of levels and Jan Westerman for on and The are to van for cannabinoid 1 conditioned medium G-protein-coupled phosphatidylinositol transfer protein phospholipase A2 sense PI-TPα wild-type NIH3T3 cells