Glycogen Synthase Kinase-3β Facilitates Staurosporine- and Heat Shock-induced Apoptosis

The potential role of glycogen synthase kinase-3β in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3β to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3β by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3β. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3β-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3β facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3β may contribute to pro-apoptotic-signaling activity, that inhibition of glycogen synthase kinase-3β can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3β. The potential role of glycogen synthase kinase-3β in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3β to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3β by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3β. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3β-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3β facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3β may contribute to pro-apoptotic-signaling activity, that inhibition of glycogen synthase kinase-3β can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3β. glycogen synthase kinase-3 phosphoinositide-dependent kinase-1 poly(ADP-ribose) polymerase hemagglutinin acetyl amidomethylcoumarin analysis of variance Glycogen synthase kinase-3 (GSK-3)1 was initially identified as a kinase that phosphorylates glycogen synthase (1.Parker P.J. Caudwell F.B. Cohen P. Eur. J. Biochem. 1983; 130: 227-234Crossref PubMed Scopus (207) Google Scholar). 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Although often considered to be a constitutively active enzyme, GSK-3β can be both activated and inhibited. Activation has been shown to occur subsequent to phosphorylation of Tyr216 (10.Hughes K. Nikolakaki E. Plyte S.E. Totty N.F. Woodgett J.R. EMBO J. 1993; 12: 803-808Crossref PubMed Scopus (521) Google Scholar) and recently by transient increases in intracellular calcium (11.Hartigan J.A. Johnson G.V.W. J. Biol. Chem. 1999; 274: 21395-21401Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). Inhibition of GSK-3β can be induced by activation of the Wnt pathway (12.Cook D. Fry M.J. Hughes K. Sumathipala R. Woodgett J.R. Dale T.C. EMBO J. 1996; 15: 4526-4536Crossref PubMed Scopus (343) Google Scholar) or by agents that activate a signaling cascade that commences when growth factors or insulin bind to their respective receptors (see Ref. 13.Coffer P.J. Jin J. Woodgett J.R. Biochem. 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Biol. 1999; 19: 5800-5810Crossref PubMed Scopus (589) Google Scholar), but it is not known whether or not inhibition of GSK-3β contributes to the anti-apoptotic effects of Akt activity. There is some evidence of the converse, that activation of GSK-3β contributes to pro-apoptotic signaling, as it was recently found that overexpression of GSK-3β in Rat-1 and PC12 cells stimulated apoptosis (23.Pap M. Cooper G.M. J. Biol. Chem. 1998; 273: 19929-19932Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar). Considering the potentially important role of GSK-3β in regulating apoptosis, it was of great interest to note that lithium was recently discovered to inhibit of GSK-3β (24.Klein P.S. Melton D.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8455-8459Crossref PubMed Scopus (2072) Google Scholar,25.Stambolic V. Ruel L. Woodgett J.R. Curr. Biol. 1996; 6: 1664-1668Abstract Full Text Full Text PDF PubMed Google Scholar). Lithium is used therapeutically for the treatment of bipolar disorder, and although it has been used in the psychiatric domain for many years, its influences at the biochemical level are only beginning to be elucidated (26.Jope R.S. Mol. Psychiatry. 1999; 4: 117-128Crossref PubMed Scopus (363) Google Scholar). One of the most intriguing findings is that lithium confers protection to neurons against pro-apoptotic stimuli such as glutamate-induced excitotoxicity (27.Nonaka S. Hough C.J. Chuang D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2642-2647Crossref PubMed Scopus (398) Google Scholar), C2-ceramide (28.Centeno F. Mora A. Fuentes J.M. Soler G. Claro E. Neuroreport. 1998; 9: 4199-4203Crossref PubMed Scopus (61) Google Scholar), radiation (29.Inouye M. Yamamura H. Nakano A. J. Radiat. Res. 1995; 36: 203-208Crossref PubMed Scopus (42) Google Scholar), and ischemia (30.Nonaka S. Chuang D.M. Neuroreport. 1998; 9: 2081-2084Crossref PubMed Scopus (263) Google Scholar). Taken together, these findings raise the possibilities that GSK-3β contributes to apoptotic-signaling cascades and that inhibition of GSK-3β contributes to the neuroprotective properties of lithium. The enzymes that ultimately carry out the command for apoptosis are the cysteine proteases known as caspases. Caspases, which are zymogens, are typically cleaved autocatalytically or by other caspases from inactive procaspase proteins to produce activated enzymes (31.Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4115) Google Scholar, 32.Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Crossref PubMed Scopus (6137) Google Scholar). Caspase-3, also called CPP32, is activated by many pro-apoptotic stimuli and is an early step in the execution phase of apoptosis (33.Harvey K.J. Blomquist J.F. Ucker D.S. Mol. Cell. Biol. 1998; 18: 2912-2922Crossref PubMed Scopus (62) Google Scholar). The activation of caspase-3 commences after apoptotic signals induce the release of cytochrome c from the mitochondrial intermembrane space (34.Green D.R. Reed J.C. Science. 1998; 281: 1309-1312Crossref PubMed Google Scholar), which subsequently associates with apoptotic protease-activating factor-1 and procaspase-9 to form the “apoptosome” (35.Zou H. Li Y. Liu X. Wang X. J. Biol. Chem. 1999; 274: 11549-11556Abstract Full Text Full Text PDF PubMed Scopus (1788) Google Scholar). This complex formation stimulates the oligomerization of procaspase-9 and its autocatalytic activation. The effect of caspase-9 activity is the proteolytic activation of downstream caspases such as caspase-3 (36.Slee E.A. Harte M.T. Kluck R.M. Wolf B.B. Casiano C.A. Newmeyer D.D. Wang H.G. Reed J.C. Nicholson D.W. Alnemri E.S. Green D.R. Martin S.J. J. Cell Biol. 1999; 144: 281-292Crossref PubMed Scopus (1671) Google Scholar), which in turn proteolyzes the DNA-binding protein poly(ADP-ribose) polymerase (PARP) (37.Tewari M. Quan L.T. O'Rourke K. Desnoyers S. Zeng Z. Beidler D.R. Poirier G.G. Salvesen G.S. Dixit V.M. Cell. 1995; 81: 801-809Abstract Full Text PDF PubMed Scopus (2268) Google Scholar) and other proteins. Hence the measurement of caspase-3 activity can serve as a biochemical marker for the execution phase of apoptosis. The goal of this investigation was to test if GSK-3β activity modulates apoptosis using the neuronal model system of human neuroblastoma SH-SY5Y cells. Apoptosis was generated using staurosporine, which previously has been demonstrated to induce apoptosis in these and other cells (38.Kruman I. Guo Q. Mattson M.P. J. Neurosci. Res. 1998; 51: 293-308Crossref PubMed Scopus (343) Google Scholar, 39.Jacobsen M.D. Weil M. J. Cell Biol. 1996; PubMed Scopus Google Scholar, R. K. R. Wang J. 1997; PubMed Scopus Google Scholar), and heat shock, a used to cell K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, A. S. Cell 1998; PubMed Scopus Google Scholar). GSK-3β activity was increased by and GSK-3β activity was by using lithium. The that overexpression of GSK-3β did not induce apoptosis, but it cells to apoptosis caused by to or to heat shock, and that inhibition of GSK-3β by lithium attenuated activation of neuroblastoma SH-SY5Y cells in and cells with that other the as in with at a of For SH-SY5Y cells The cells from the with of with and for at in was to with and with of in by J. R. of on for was out with a at and as previously H. L. P. Proc. Natl. Acad. Sci. U. S. A. 81: PubMed Scopus Google Scholar). cells on for and with of and a the was with and the cells in for only cells to and for of For cells in with and with of and For activity, cells with of The in and in the using the The at used for or activity. Cell with and in a for in for GSK-3β and caspase-9 or in and for and caspase-3, The proteins to with to GSK-3β, caspase-3, caspase-9, or by with using and by The activity of GSK-3β was as previously Lint J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, L. C.J. M. J.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). in and The in for on and at for the protein was of protein was with of protein for at with of GSK-3β at with The three times with and with activity was in a of of kinase of and synthase Glycogen synthase was used as The at for the for and of The times in for a of in and in a The of GSK-3β was by for GSK-3β. in and out in well of was for caspase-3 caspase-9 or to well to a of the caspase-3 was it was at a of the of the caspase-3 Cell of to the was in and the cell at for for measurement of caspase-3 and for measurement of and caspase-9, on of the to of was on a at and activity was as from of on in was and the cells in for at two with cells with for at The with and using The examined by at the of cells apoptotic a of cells SH-SY5Y cells with and examined for associated with apoptosis, including activation of proteolysis of and changes in cellular activity increased after treatment with to of the activation of caspases induced by that caspase-3 activity to after treatment and activation after The of the caspase-3 was by the of a caspase-3 which in the inhibition of caspase-3 activity. and also to test if other caspases activated by treatment. activity to after of treatment and a but was not The proteolytic of to the after treatment with to the activation of caspase-3 of cells with for and with the associated with apoptosis, such as and cell test the that GSK-3β facilitates apoptosis, SH-SY5Y cells with GSK-3β, and several cell the levels of GSK-3β, and procaspase-9 in control cells, cells, and cell of cells. are evident on the GSK-3β than GSK-3β due to the In these cell GSK-3β and of the GSK-3β in cells and cells, The activity of GSK-3β was also in cell In the cell GSK-3β activity and of the GSK-3β in and cells, In cells, the levels of and and the level of procaspase-9 and that of the levels of these caspases in cells and cells, out using cell and using the other three cell The concentration-dependent activation of caspase-3 was after treatment in cells and in the of cells. caspase-3 activities in and cells not from control SH-SY5Y cells. In cells, activation of caspase-3 by was to that in SH-SY5Y cells In overexpression of potentiated staurosporine-induced activation of caspase-3 in cells overexpressing GSK-3β. The caspase-3 activity in cells and of that in cells after treatment with and staurosporine, caspase-9 activity in cells and of that in cells after treatment with and staurosporine, The of staurosporine-induced caspase-3 activity by GSK-3β overexpression was by a greater of proteolysis and greater of cells apoptotic and These indicate that overexpression of increases the of cells to staurosporine-induced apoptosis. with lithium to inhibit GSK-3β to test if inhibition of GSK-3β staurosporine-induced activation of caspase-3 in control or cells. The in the of that activated caspase-3 in control and cells it to for cell caspase-3 was in cells after treatment with and in cells after treatment with SH-SY5Y cells with and for and with for of control SH-SY5Y cells with lithium staurosporine-induced caspase-3 activity by cells for B) or for with or lithium. for with lithium the staurosporine-induced caspase-3 activity by treatment with and lithium in of and of caspase-3 activity induced by These that the effect of GSK-3β on staurosporine-induced caspase-3 activity is attenuated by lithium. test if the by and by lithium of caspase-3 activation occur with apoptotic the effects of these in cells subjected to heat shock at by at a model used to the of cells to K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, A. S. Cell 1998; PubMed Scopus Google Scholar). In cells caspase-3 activity increased to and that of the basal activity and of at In cells, caspase-3 activity increased to and that of the basal activity after and of at of cells with and Li for the heat caspase-3 activation by and These that overexpression of GSK-3β the activation of caspase-3 after treatment with heat shock and that with a GSK-3β this In to its beginning as a of glycogen GSK-3β has been found to in a of signaling on the findings the cell and Thus, cells overexpressing GSK-3β more to the actions of or to than did cells with a of GSK-3β. an of GSK-3β, the of apoptosis caused by overexpression of GSK-3β. These findings that in the apoptotic signaling activation of caspases can be by GSK-3β. Staurosporine is of the most used agents to induce apoptosis, and apoptosis in cell to of staurosporine, that it a cell to cells (38.Kruman I. Guo Q. Mattson M.P. J. Neurosci. Res. 1998; 51: 293-308Crossref PubMed Scopus (343) Google Scholar). Staurosporine previously has been to induce apoptosis in human neuroblastoma SH-SY5Y cells R. K. R. Wang J. 1997; PubMed Scopus Google Scholar, I. J.P. J. 1999; PubMed Scopus Google Scholar). In these cells, was to caspase-3 activity, in and morphological changes indicative of apoptosis a of treatment R. K. R. Wang J. 1997; PubMed Scopus Google Scholar), effects also in this a concentration-dependent activation of caspase-3 the of to In cells overexpressing GSK-3β, the concentration-dependent activation of caspase-3 and of caspase-9 was to the greater activation of these caspases after treatment with of These findings that GSK-3β facilitated staurosporine-induced apoptosis. This was by the findings of greater proteolysis and morphological changes apoptotic cells in cells than control cells after to the GSK-3β attenuated the of staurosporine-induced caspase-3 activity in cells overexpressing GSK-3β. Taken together, these that GSK-3β is a of the cascade induced by of and Cooper (23.Pap M. Cooper G.M. J. Biol. Chem. 1998; 273: 19929-19932Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar), recently evidence that GSK-3β is In their transient of GSK-3β in PC12 cells and Rat-1 caused to of cells to apoptosis with treatment in a from of and Cooper (23.Pap M. Cooper G.M. J. Biol. Chem. 1998; 273: 19929-19932Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar) in that a overexpression of GSK-3β to alter caspase-3 activity or cell a that may be due to cell to the of GSK-3β or to in the levels of GSK-3β, which not by and Cooper (23.Pap M. Cooper G.M. J. Biol. Chem. 1998; 273: 19929-19932Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar). of this both studies the that GSK-3β is an important modulator of cell In to staurosporine-induced apoptosis, overexpression of GSK-3β and lithium treatment caspase-3 activation of cells to heat variety of are in cells to the of as by heat shock, such as in the activities of signaling protein and of the of heat shock proteins (see Ref. A.B. J.A. FEBS Lett. 1998; PubMed Scopus Google Scholar for In SH-SY5Y cells as well as many other of cells, the to a of heat shock are to caspase-3 activation was heat shock in control cells in this activation of phosphatidylinositol 3-kinase B.B. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) and of GSK-3β M. Cohen P. Alessi D.R. Biochem. J. 1998; PubMed Scopus Google Scholar) have been to heat shock, that may with to protection from heat The of the that of GSK-3β is for cell as GSK-3β in a activation of caspase-3 heat shock, inhibition of GSK-3β by lithium in cells overexpressing cells from heat caspase-3 activation. The two that activation of GSK-3β facilitates apoptosis, and that the anti-apoptotic actions of agents that the phosphatidylinositol pathway H. Datta S.R. Franke T.F. Birnbaum M.J. Yao R. Cooper G.M. Segal R.A. Kaplan D.R. Greenberg M.E. Science. 1997; 275: 661-665Crossref PubMed Scopus (2215) Google Scholar) may be due in part to the inhibitory effect of phosphatidylinositol signaling on GSK-3β activity. The mechanism by which GSK-3β activity contributes to and increased GSK-3β activity contributes to apoptosis remains One mechanism is the regulation by GSK-3β of GSK-3β activity facilitates of β-catenin H. A. J. A. R. 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Although lithium has been to a variety of other (26.Jope R.S. Mol. Psychiatry. 1999; 4: 117-128Crossref PubMed Scopus (363) Google Scholar) that be as the effects of lithium in cells that inhibition of GSK-3β for the protection from apoptosis by lithium. the several studies in R.S. Mol. Psychiatry. 1999; 4: 117-128Crossref PubMed Scopus (363) Google Scholar), from Chuang and have shown that lithium protects neurons from the effects of a wide variety of such as ischemia (30.Nonaka S. Chuang D.M. Neuroreport. 1998; 9: 2081-2084Crossref PubMed Scopus (263) Google Scholar) and activation of receptors (27.Nonaka S. Hough C.J. Chuang D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2642-2647Crossref PubMed Scopus (398) Google Scholar, Chuang D.M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The findings in this raise the that these neuroprotective actions of lithium may occur at in part of its to inhibit GSK-3β. In the for the that increases in GSK-3β apoptosis in two model including apoptosis induced by and by heat the inhibitory effect of lithium on GSK-3β and its of apoptosis that some of the neuroprotective effects of lithium may from this J. R. Woodgett for the