Stimulation of Phosphatidylserine Biosynthesis and Facilitation of UV-induced Apoptosis in Chinese Hamster Ovary Cells Overexpressing Phospholipid Scramblase 1

Members of the phospholipid scramblase (PLSCR) family play active roles in altering lipid asymmetry at the plasma membrane including phosphatidylserine (PtdSer) exposure on the cell surface. To determine whether PtdSer biosynthesis and externalization are altered by PLSCR activities during apoptosis, Chinese hamster ovary K1 cell lines stably overexpressing PLSCR1 and PLSCR2 were established. PLSCR1 was localized on the plasma membrane, whereas PLSCR2 was predominantly in the nucleus. Cells overexpressing PLSCR1 showed suppressed growth, altered cell morphology, and higher basal levels of cell death. Following UV irradiation, these cells showed earlier and enhanced PtdSer exposure, increased caspase-3 activation, apoptotic nuclear changes, and PARP cleavage indicative of apoptosis. UV irradiation in cells overexpressing PLSCR1 led to a 4-fold stimulation of PtdSer synthesis (accompanied by increased movement of newly made PtdSer into microvesicles) relative to untreated PLSCR1 cells, whereas PtdSer formation in UV-irradiated vector control cells increased only by 2-fold. No differences in these responses were observed between PLSCR2-expressing cells and vector controls. PtdSer synthesis and its transbilayer movement stimulated by PLSCR1 overexpression were blocked by a caspase inhibitor along with progression of apoptosis. Thus, our studies showed that overexpression of PLSCR1 in Chinese hamster ovary K1 cells stimulated caspase-dependent PtdSer externalization and synthesis, implying an up-regulation of PtdSer formation in response to enhanced outward movement of this phospholipid to the cell surface during apoptosis. PLSCR1 also appears to influence progression of UV-induced apoptosis and could be a point of regulation or intervention during programmed cell death. Members of the phospholipid scramblase (PLSCR) family play active roles in altering lipid asymmetry at the plasma membrane including phosphatidylserine (PtdSer) exposure on the cell surface. To determine whether PtdSer biosynthesis and externalization are altered by PLSCR activities during apoptosis, Chinese hamster ovary K1 cell lines stably overexpressing PLSCR1 and PLSCR2 were established. PLSCR1 was localized on the plasma membrane, whereas PLSCR2 was predominantly in the nucleus. Cells overexpressing PLSCR1 showed suppressed growth, altered cell morphology, and higher basal levels of cell death. Following UV irradiation, these cells showed earlier and enhanced PtdSer exposure, increased caspase-3 activation, apoptotic nuclear changes, and PARP cleavage indicative of apoptosis. UV irradiation in cells overexpressing PLSCR1 led to a 4-fold stimulation of PtdSer synthesis (accompanied by increased movement of newly made PtdSer into microvesicles) relative to untreated PLSCR1 cells, whereas PtdSer formation in UV-irradiated vector control cells increased only by 2-fold. No differences in these responses were observed between PLSCR2-expressing cells and vector controls. PtdSer synthesis and its transbilayer movement stimulated by PLSCR1 overexpression were blocked by a caspase inhibitor along with progression of apoptosis. Thus, our studies showed that overexpression of PLSCR1 in Chinese hamster ovary K1 cells stimulated caspase-dependent PtdSer externalization and synthesis, implying an up-regulation of PtdSer formation in response to enhanced outward movement of this phospholipid to the cell surface during apoptosis. PLSCR1 also appears to influence progression of UV-induced apoptosis and could be a point of regulation or intervention during programmed cell death. Phosphatidylserine (PtdSer) 1The abbreviations used are: PtdSer, phosphatidylserine; CHO, Chinese hamster ovary; mAb, monoclonal antibody; pAb, polyclonal antibody; PARP, poly(ADP-ribose) polymerase; PLSCR, phospholipid scramblase; PtdEtn, phosphatidylethanolamine; SM, sphingomyelin; z-VAD-fmk, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone; PSS, PtdSer synthase; PI, propidium iodide; TBS, Tris-buffered saline; PBS, phosphate-buffered saline; BSA, bovine serum albumin 1The abbreviations used are: PtdSer, phosphatidylserine; CHO, Chinese hamster ovary; mAb, monoclonal antibody; pAb, polyclonal antibody; PARP, poly(ADP-ribose) polymerase; PLSCR, phospholipid scramblase; PtdEtn, phosphatidylethanolamine; SM, sphingomyelin; z-VAD-fmk, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone; PSS, PtdSer synthase; PI, propidium iodide; TBS, Tris-buffered saline; PBS, phosphate-buffered saline; BSA, bovine serum albuminexternalization is observed during cell activation, aging, and apoptosis (1Bevers E.M. Comfurius P. van Rijn J.L. Hemker H.C. Zwaal R.F. Eur. J. Biochem. 1982; 122: 429-436Google Scholar, 2Connor J. Pak C.C. Schroit A.J. J. Biol. Chem. 1994; 269: 2399-2404Google Scholar, 3Martin S.J. Reutelingsperger C.P. McGahon A.J. Rader J.A. van Schie R.C. LaFace D.M. Green D.R. J. Exp. Med. 1995; 182: 1545-1556Google Scholar). This membrane lipid rearrangement may have various roles depending on the cell type and conditions for mobilization of PtdSer (4Zwaal R.F. Schroit A.J. Blood. 1997; 89: 1121-1132Google Scholar). When exposed on the cell surface during programmed cell death, PtdSer signals the removal of apoptotic cells to avoid inflammatory reactions (5Fadok V.A. Voelker D.R. Campbell P.A. Cohen J.J. Bratton D.L. Henson P.M. J. Immunol. 1992; 148: 2207-2216Google Scholar, 6Fadok V.A. Bratton D.L. Frasch S.C. Warner M.L. Henson P.M. Cell Death Differ. 1998; 5: 551-562Google Scholar). Phospholipid scrambling also leads to inward movement of sphingomyelin (SM), where it may be hydrolyzed by neutral sphingomyelinase; subsequent production of ceramide may play an important role in membrane blebbing during apoptosis (7Tepper A.D. Ruurs P. Wiedmer T. Sims P.J. Borst J. van Blitterswijk W.J. J. Cell Biol. 2000; 150: 155-164Google Scholar). Mechanisms underlying PtdSer externalization are unclear, but concomitant inactivation of aminophospholipid translocase activity and activation of phospholipid scramblase (PLSCR) as a result of rising concentrations of cytoplasmic calcium are considered to play a major role (8Bevers E.M. Comfurius P. Dekkers D.W. Harmsma M. Zwaal R.F. Lupus. 1998; 7: S126-S131Google Scholar, 9Bevers E.M. Comfurius P. Dekkers D.W. Harmsma M. Zwaal R.F. Biol. Chem. 1998; 379: 973-986Google Scholar, 10Bevers E.M. Comfurius P. Dekkers D.W. Zwaal R.F. Biochim. Biophys. Acta. 1999; 1439: 317-330Google Scholar). Aminophospholipid translocase helps to maintain membrane asymmetry by moving PtdSer and PtdEtn on the outer leaflet back to the inner membrane bilayer (11Seigneuret M. Devaux P.F. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3751-3755Google Scholar, 12Zachowski A. Favre E. Cribier S. Herve P. Devaux P.F. Biochemistry. 1986; 25: 2585-2590Google Scholar, 13Morrot G. Herve P. Zachowski A. Fellmann P. Devaux P.F. Biochemistry. 1989; 28: 3456-3462Google Scholar). Phospholipid scramblase, when activated, catalyzes bidirectional movement of all of the membrane phospholipids (14Smeets E.F. Comfurius P. Bevers E.M. Zwaal R.F. Biochim. Biophys. Acta. 1994; 1195: 281-286Google Scholar, 15Williamson P. Bevers E.M. Smeets E.F. Comfurius P. Schlegel R.A. Zwaal R.F. Biochemistry. 1995; 34: 10448-10455Google Scholar, 16Stout J.G. Basse F. Luhm R.A. Weiss H.J. Wiedmer T. Sims P.J. J. Clin. Invest. 1997; 99: 2232-2238Google Scholar). A family of phospholipid scramblases, including HuPLSCR 1–4 and their murine orthologs, MuPLSCR 1–4, as well as a rat PLSCR homolog to HuPLSCR1, has been identified (17Wiedmer T. Zhou Q. Kwoh D.Y. Sims P.J. Biochim. Biophys. Acta. 2000; 1467: 244-253Google Scholar, 18Pastorelli C. Veiga J. Charles N. Voignier E. Moussu H. Monteiro R.C. Benhamou M. J. Biol. Chem. 2001; 276: 20407-20412Google Scholar). PLSCR proteins have a short extracellular domain or no extracellular domain, whereas their intracellular domains are highly variable in length and composition (18Pastorelli C. Veiga J. Charles N. Voignier E. Moussu H. Monteiro R.C. Benhamou M. J. Biol. Chem. 2001; 276: 20407-20412Google Scholar). Expression of PLSCR1 is induced at the transcriptional level by interferon, indicating its potential involvement in interferon-mediated activities (19Zhou Q. Zhao J. Al Zoghaibi F. Zhou A. Wiedmer T. Silverman R.H. Sims P.J. Blood. 2000; 95: 2593-2599Google Scholar, 20Silverman R.H. Halloum A. Zhou A. Dong B. Al Zoghaibi F. Kushner D. Zhou Q. Zhao J. Wiedmer T. Sims P.J. Cancer Res. 2002; 62: 397-402Google Scholar). The PLSCRs are type II transmembrane proteins that are highly conserved in the calcium-binding C-terminal domain (21Zhou Q. Sims P.J. Wiedmer T. Biochemistry. 1998; 37: 2356-2360Google Scholar). Calcium binding to the proteins is presumed to induce a major conformational change and activate the lipid scrambling activity (22Stout J.G. Zhou Q. Wiedmer T. Sims P.J. Biochemistry. 1998; 37: 14860-14866Google Scholar). Some members contain PXXP and PPXY motifs, indicating potential interaction with signaling molecules that contain SH3 or WW domains (17Wiedmer T. Zhou Q. Kwoh D.Y. Sims P.J. Biochim. Biophys. Acta. 2000; 1467: 244-253Google Scholar, 23Sims P.J. Wiedmer T. Thromb. Haemostasis. 2001; 86: 266-275Google Scholar). PLSCR1 binds to the SH3 domain of c-Ab1 tyrosine kinase and is constitutively tyrosine phosphorylated by this enzyme (24Sun J. Zhao J. Schwartz M.A. Wang J.Y. Wiedmer T. Sims P.J. J. Biol. Chem. 2001; 276: 28984-28990Google Scholar). PLSCR1 is also found to be enriched in lipid rafts and phosphorylated upon its interaction with epidermal growth factor receptor (25Sun J. Nanjundan M. Pike L.J. Wiedmer T. Sims P.J. Biochemistry. 2002; 41: 6338-6345Google Scholar). Other post-translational modifications of PLSCR implicated in regulating its normal functions include palmitoylation at multiple cysteine residues (26Zhao J. Zhou Q. Wiedmer T. Sims P.J. Biochemistry. 1998; 37: 6361-6366Google Scholar) and phosphorylation at one threonine site through protein kinase Cδ (27Frasch S.C. Henson P.M. Kailey J.M. Richter D.A. Janes M.S. Fadok V.A. Bratton D.L. J. Biol. Chem. 2000; 275: 23065-23073Google Scholar). PLSCR proteins only to activate membrane lipid scrambling but also play roles in signaling that as and R.H. Halloum A. Zhou A. Dong B. Al Zoghaibi F. Kushner D. Zhou Q. Zhao J. Wiedmer T. Sims P.J. Cancer Res. 2002; 62: 397-402Google Scholar, J. Zhao J. Schwartz M.A. Wang J.Y. Wiedmer T. Sims P.J. J. Biol. Chem. 2001; 276: 28984-28990Google Scholar). cells showed that PtdSer biosynthesis increased along with the exposure of PtdSer on the cell surface during apoptosis induced by various with newly PtdSer into apoptotic This stimulation of synthesis is in a caspase-dependent A. D.M. Biochim. Biophys. Acta. 2000; Scholar). PtdSer synthesis at the and through with the of phospholipids J. Biol. Chem. by of PtdSer with whereas II PtdEtn to PtdSer M. Biochim. Biophys. Acta. 1997; Scholar). PtdSer is to including the plasma PtdSer also is to where it be to of PtdSer biosynthesis and its movement in cells is well cells, control appears to reactions to maintain levels of The cells PtdSer synthesis of PtdSer by a M. J. Biol. Chem. 1986; Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: Scholar, M. J. Biol. Chem. 1999; Scholar). that PtdSer exposure on the cell surface and subsequent movement into may the for PtdSer as intracellular PtdSer levels of PtdSer biosynthesis in response to the PtdSer scrambling To a role of PLSCR, cell lines overexpressing PLSCR1 and PLSCR2 and biosynthesis of phospholipids and their movement into the during UV-induced apoptosis. studies that PLSCR activity synthesis and of PtdSer in an and caspase-dependent during apoptosis. was poly(ADP-ribose) was was was was and propidium were was and were was the The cells were in a in with bovine serum and Cells in growth were with and in with The cells were exposed to a predominantly for and for of PLSCR1 was by Sims (17Wiedmer T. Zhou Q. Kwoh D.Y. Sims P.J. Biochim. Biophys. Acta. 2000; 1467: 244-253Google Scholar, Q. Zhao J. J.G. Luhm R.A. Wiedmer T. Sims P.J. J. Biol. Chem. 1997; Scholar). PLSCR2 homolog was and that all were the as in for a highly conserved at (21Zhou Q. Sims P.J. Wiedmer T. Biochemistry. 1998; 37: 2356-2360Google Scholar). and were into the and of the of PLSCR1 by with and and were to the and of the of PLSCR2 by with and were into the vector and by were into the A vector to the and cells to were with or of to the The cells were for To the of cells were with vector and or to the of and of was to the cells, and the was the of Cell was observed by were by and by and The cells overexpressing and vector control were in growth of and of Cells were with Tris-buffered PARP the cell were by cells in of scramblase protein were by cells in of inhibitor in by on for The cell was at for at in a was with of The protein of was a protein The were by for PARP and for PLSCR1 and and to membrane to the PARP the membrane was for with PARP in with in The was with and for with in with of the membrane was with to the The was with was used to proteins to the The cells were exposed to UV for and for The cells were and with the The cells were by at for and were in in the of an of the of cells was a The cells were on the cells were with and with in for at The cells were with in at and with was and for at The cells were with The were in and in on of activation of caspase was with with at by with at was with the and for was with at and was with at a were with of cells with of of or of for various the was and The cells were with of PBS, and were with the The cells were by in of The were cell and a J. M. J. Biol. Chem. Scholar, D.M. Biochim. Biophys. Acta. Scholar). in lipid was a were with a of and with a phospholipid was by of the lipid G. S. Scholar). phospholipid biosynthesis was to in the lipid The or were as the and the differences were Cells on were with and was to the with binding to and PI, the cells were with for and with The were on the of a a and a were with the were with removal of the the cell was by cells in of and for on The were at at for The cell was to an of and of and at for M. J. Biol. Chem. 1986; Scholar). The reactions were by of and of The were and at for was a and the was a was a studies that PLSCR1 be in cells by and no scramblase activity is by in (27Frasch S.C. Henson P.M. Kailey J.M. Richter D.A. Janes M.S. Fadok V.A. Bratton D.L. J. Biol. Chem. 2000; 275: 23065-23073Google Scholar). cells were with or and stably overexpressing PLSCR1 and PLSCR2 were to the that cells overexpressing PLSCR were by cells where only the was used a to and cells by cells with vector PLSCR and an vector a this were of a C-terminal that the proteins could be by and an A protein was in with or PLSCR2 and with No protein with was by of these cells showed a predominantly plasma membrane of PLSCR1 cells in cells, highly PLSCR1 also was in the cell nucleus. also was observed in cells overexpressing PLSCR1 PLSCR2 was found predominantly in the but also was in the in vector control cells the of PLSCR proteins our that stably overexpressing PLSCR1 and PLSCR2 were and that the levels of and of the proteins could be with with the were used in the When cells were at and for for their growth vector control cells to the type cells, whereas cells overexpressing PLSCR1 at a by cell growth was by with vector control cells The of cells was that of type cells, the and PLSCR2-expressing cells were vector control cells and a growth or between PLSCR2-expressing cells in a growth with the vector control When apoptosis was induced in cells overexpressing PLSCR1 or PLSCR2 by to UV for cells overexpressing PLSCR1 earlier of apoptotic vector UV irradiation, when a of control cells with vector showed of apoptosis, the cells and cell was PLSCR2-expressing cells major differences in apoptotic cell with vector When cell was with a cells showed a higher basal level of cell death, and UV in cells, whereas no cell was observed in UV of vector cells UV irradiation To activation as a for the progression of apoptosis, that only active caspase-3 was used to caspase activation in and vector cells A higher basal level of cell by PLSCR1 overexpression was of the cells showed of active caspase-3 activation of caspase-3 was observed in PLSCR1 cells, whereas only a vector cells showed signals of caspase-3 of UV and also were observed in apoptotic cells that showed for caspase-3 No differences in caspase-3 activation and nuclear were observed with PLSCR2-expressing cells with vector Thus, PLSCR1 overexpression growth and UV-induced apoptosis in cells, whereas PLSCR2 protein have PLSCR1 is in phospholipids at the plasma of PLSCR1 in cells in a higher basal level of PtdSer whereas PtdSer on the cell surface in vector control cells UV irradiation When apoptosis was induced with UV irradiation, PtdSer levels on the surface of PLSCR1 cells increased as as the of PLSCR1 cells showed indicating major PtdSer whereas vector cells showed The of cell was and cells were with propidium in their PLSCR2-expressing cells major differences in exposure of PtdSer with vector cells with or UV PtdSer externalization also was by the of in UV-irradiated and vector cells Thus, PLSCR1 overexpression apoptosis and increased PtdSer externalization in cells UV irradiation in a caspase-dependent whereas PLSCR2 overexpression to PtdSer externalization or cell death. with cells showed that synthesis of PtdSer was stimulated during programmed cell induced by various of apoptosis A. D.M. Biochim. Biophys. Acta. 2000; Scholar). that stimulation of PtdSer biosynthesis also was observed in cells during UV-induced apoptosis. To the that PtdSer biosynthesis and externalization to the cell surface were and that increased outward movement of PtdSer may PtdSer the biosynthesis of PtdSer and phospholipids cells overexpressing PLSCR1 or UV irradiation of cells by a with was a in PtdSer synthesis in vector cells with UV PLSCR2-expressing cells basal and of PtdSer biosynthesis to control UV irradiation, the basal of PtdSer synthesis was higher in cells overexpressing UV stimulation was a in PtdSer biosynthesis in cells overexpressing PtdSer biosynthesis was 4-fold higher with untreated PtdSer to PtdEtn UV irradiation in vector and PLSCR2-expressing cells, was increased in indicating increased of newly PtdSer into the biosynthesis was stimulated in UV-irradiated PLSCR1 or PLSCR2-expressing cells and in vector cells UV irradiation A higher of newly PtdSer also was during with cells with vector of PtdSer in UV Cell and were as for the was and the were and by in PtdSer was The are the of were to the involvement of altered PtdSer levels in regulating PtdSer biosynthesis in cells overexpressing PLSCR1 cells showed higher activities with vector UV change the activities of PtdSer in these A was in vector cells with untreated vector into untreated vector vector cells overexpressing PLSCR1 and vector cells were or with UV and for The cell were and as The are the of The level of was a for untreated vector vector in a cells overexpressing PLSCR1 and vector cells were or with UV and for The cell were and as The are the of The level of was a for biosynthesis of with was in cells by UV whereas no change was observed in control PtdEtn biosynthesis was in control cells and in PLSCR1 cells with UV Thus, overexpression of PLSCR1 cells in a in PtdSer biosynthesis UV-induced apoptosis, and newly PtdSer was at a higher into as and PtdEtn biosynthesis in cells overexpressing PLSCR1 through and cells overexpressing PLSCR1 and control were in Following with or UV irradiation for or was to The cells were for and as the were and by in or PtdEtn was The are the of The level of was a for controls. in a cells overexpressing PLSCR1 and control were in Following with or UV irradiation for or was to The cells were for and as the were and by in or PtdEtn was The are the of The level of was a for of PtdSer biosynthesis in type cells during UV-induced apoptosis was of caspase activation and was blocked by z-VAD-fmk, a caspase inhibitor Cells overexpressing PLSCR1 showed basal levels of PARP a for caspase-3 When was to cells UV irradiation, apoptosis was blocked in vector and cells, on a of PARP cleavage of PtdSer biosynthesis was in the of in vector cells to type PtdSer biosynthesis stimulated in cells was by to a level to that of the vector cells, indicating that stimulation of PtdSer biosynthesis as a result of PLSCR1 overexpression was blocked by of newly PtdSer into was to in vector and cells showed on PtdSer in vector and cells with or UV synthesis in vector cells was by z-VAD-fmk, but the caspase inhibitor increased stimulation in cells to the level to that of the vector cells Thus, stimulation of PtdSer biosynthesis in PLSCR1 cells was on caspase activation, but were in PtdSer biosynthesis in vector cells of apoptosis by UV of PtdSer on the cell surface is a for removal of apoptotic studies showed that transbilayer of PtdSer was with PtdSer synthesis by a caspase-dependent A. D.M. Biochim. Biophys. Acta. 2000; Scholar). To the between PtdSer externalization and its the involvement of PLSCR for active of PtdSer to the cell surface in regulating PtdSer overexpression of PLSCR were in PLSCR1 be in cells by and no scramblase activity is by in (27Frasch S.C. Henson P.M. Kailey J.M. Richter D.A. Janes M.S. Fadok V.A. Bratton D.L. J. Biol. Chem. 2000; 275: 23065-23073Google that of PLSCR to the cells by PtdSer synthesis its externalization in response to of apoptosis. When in cells, PLSCR1 was predominantly in the plasma membrane of the cell in in the at conserved in PLSCR1 is for this protein to the plasma membrane (26Zhao J. Zhou Q. Wiedmer T. Sims P.J. Biochemistry. 1998; 37: 6361-6366Google PLSCR1 proteins by palmitoylation may be into the of PLSCR1 in in cell morphology, increased basal cell death, and of cell cells also higher basal levels of PtdSer on the cell surface. blebbing also was observed in these When PLSCR1 is stably in cell R.H. Halloum A. Zhou A. Dong B. Al Zoghaibi F. Kushner D. Zhou Q. Zhao J. Wiedmer T. Sims P.J. Cancer Res. 2002; 62: 397-402Google no in growth and are found in cells in serum but of is observed when cells are into R.H. Halloum A. Zhou A. Dong B. Al Zoghaibi F. Kushner D. Zhou Q. Zhao J. Wiedmer T. Sims P.J. Cancer Res. 2002; 62: 397-402Google Scholar). that PLSCR1 cell growth in serum cell The or of in PLSCR1 overexpressing cells are but increased membrane lipid movement and blebbing may to the observed PtdSer is found to be exposed in membrane in membrane P.M. Bratton D.L. Fadok V.A. Biol. 2001; indicating that higher PLSCR1 activity may PtdSer to these surface When apoptosis was induced by UV irradiation, cells and earlier the vector PLSCR1 cells exposed PtdSer to the by UV of the cells overexpressing PLSCR1 showed whereas control cells exposed caspase-3 activation earlier in PLSCR1 cells with controls. nuclear in PLSCR1 cells that in control these differences that PLSCR1 an important role in PtdSer externalization of apoptosis. Thus, PLSCR1 be considered to be and as overexpression leads to of growth and cell in untreated cells and apoptosis in UV-induced To determine between increased PtdSer movement to the outer surface and synthesis of PtdSer, lipid biosynthesis was as a on and of by cells, overexpressing PLSCR1 showed higher basal levels of PtdSer biosynthesis and externalization with vector control of activity that activities in conditions may the for synthesis in cells a localized of in or that an in enzyme activity in cells may to the higher basal levels of PtdSer biosynthesis in Following UV irradiation of cells, the stimulation of PtdSer biosynthesis by was higher in cells with control cells and newly PtdSer into apoptotic cells overexpressing PLSCR1 a in PtdSer synthesis with vector an in PtdSer level could be by a of PtdSer but this was the synthesis of PtdEtn was enhanced in cells UV irradiation, indicating increased of PtdSer into no major in were observed in cells and vector cells UV irradiation a activities of in in apoptotic cells upon UV indicating that an in the of may be the underlying the stimulation of PtdSer biosynthesis observed in cell This that in PtdSer biosynthesis during of apoptosis an in the of one of this that activation of PtdSer externalization to the cell surface of cells, through overexpression of may PtdSer to activity and PtdSer biosynthesis in untreated and cells a change in of of PtdSer to the outer leaflet of the plasma membrane and its into may PtdSer on the inner surface of the membrane This may a for enhanced PtdSer biosynthesis as of the production of PtdSer is to the on PtdSer synthesis, cells only a in formation with control cells and a stimulation UV that of PtdSer biosynthesis and are to a in cells overexpressing PLSCR1 the biosynthesis as a the cells and the stimulation of PtdSer synthesis UV irradiation of caspase Other studies in our that stimulation of PtdSer synthesis in cells, by or caspase C. D. M. N. D. and H. the the 4-fold stimulation of PtdSer formation in cells to have caspase-dependent and as of PtdSer levels in cells back to that of the control cells but it to the level of untreated The appears to be PtdSer externalization by The activation of it only to caspase when its activity is by PtdSer through of When a of scramblase an extracellular was the protein was found predominantly the nucleus. PLSCR2 overexpression PtdSer externalization or PtdSer biosynthesis in cells during UV-induced apoptosis. This that PtdSer externalization leads to the stimulation of PtdSer PLSCR2 when into in has been to scrambling to PLSCR (21Zhou Q. Sims P.J. Wiedmer T. Biochemistry. 1998; 37: 2356-2360Google Scholar). PLSCR2 was to the of our cells, and its in the is to influence PtdSer externalization and apoptosis. our that when in cells, externalization of PtdSer at the plasma membrane and UV-induced apoptosis. The PLSCR2 is to the where its role is PtdSer biosynthesis is stimulated in cells induced to apoptosis. This stimulation is on caspase activation, by by altered levels of PtdSer on the inner surface of the plasma membrane to activity levels of the Thus, PLSCR1 at the plasma membrane appears to be a point of control in regulating the apoptotic and may a that in enhanced biosynthesis to PtdSer synthesis may be for apoptosis. is that the externalization of PtdSer by altered scramblase activities is a potential point of regulation and a for intervention in the of programmed cell and removal of cells and the by response Sims the for the of and The of and with cell is

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