Phosphoinositide 3-OH Kinase (PI3K) and PKB/Akt Delay the Onset of p53-mediated, Transcriptionally Dependent Apoptosis

The phosphoinositide 3-OH kinase (PI3K)-PKB/Akt signaling pathway has been shown to mediate both Ras- and cytokine-induced protection from apoptosis. In addition, apoptosis induced by the p53 tumor suppressor protein can be inhibited by Ras- and cytokine-mediated signaling pathways. It was therefore of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. We demonstrate in this report that constitutively active PI3K and PKB/Akt are capable of significantly delaying the onset of p53-mediated apoptosis. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. Moreover, we found that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. Our results provide the first direct and unambiguous link between p53-mediated apoptosis and the PI3K-PKB/Akt signaling pathway. The phosphoinositide 3-OH kinase (PI3K)-PKB/Akt signaling pathway has been shown to mediate both Ras- and cytokine-induced protection from apoptosis. In addition, apoptosis induced by the p53 tumor suppressor protein can be inhibited by Ras- and cytokine-mediated signaling pathways. It was therefore of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. We demonstrate in this report that constitutively active PI3K and PKB/Akt are capable of significantly delaying the onset of p53-mediated apoptosis. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. Moreover, we found that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. Our results provide the first direct and unambiguous link between p53-mediated apoptosis and the PI3K-PKB/Akt signaling pathway. phosphoinositide 3-OH kinase insulin-like growth factor interleukin baby rat kidney N-2-hydroxy-1,1-bis(hydroxymethyl)ethylglycine fluorescence-activated cell sorter The serine/threonine protein kinase PKB/Akt was originally identified as the cellular counterpart of the v-Akt transforming protein present in AKT8, a retrovirus that causes T cell lymphomas in mice (1Staal S.P. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 5034-5037Crossref PubMed Scopus (635) Google Scholar). v-Akt was generated by a fusion event that juxtaposes the retroviral glycosaminoglycan protein and the entire coding region of PKB/Akt (2Coffer P.J. Jin J. Woodgett J.R. Biochem. J. 1998; 335: 1-13Crossref PubMed Scopus (966) Google Scholar, 3Bellacosa A. Franke T.F. Gonzalez-Portal M.E. Datta K. Taguchi T. Gardner J. Cheng J.Q. Testa J.R. Tsichlis P.N. Oncogene. 1993; 8: 745-754PubMed Google Scholar). The fusion protein, designated glycosaminoglycan-PKB, is constitutively active due to a myristoylation signal present within the amino terminus of the glycosaminoglycan protein that targets PKB/Akt to the plasma membrane.In quiescent or serum-starved cells, PKB/Akt resides within the cytosol in a catalytically inactive state. Upon stimulation of cells with growth factors and cytokines, PKB/Akt is recruited to the plasma membrane and catalytically activated by phosphorylation at threonine 308 and serine 473 (4Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2495) Google Scholar, 5Stokoe D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar, 6Stephens L. Anderson K. Stokoe D. Erdjument-Bromage H. Painter G.F. Holmes A.B. Gaffney P.R. Reese C.B. McCormick F. Tempst P. Coadwell J. Hawkins P.T. Science. 1998; 279: 710-714Crossref PubMed Scopus (910) Google Scholar, 7Alessi D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar, F. J. Biol. 1996; PubMed Scopus Google Scholar). of PKB/Akt at threonine 308 is by the and constitutively active protein kinase D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar, 7Alessi D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar). The kinase phosphorylation of PKB/Akt at serine 473 has been been M. L. Woodgett J. S. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). of both PKB/Akt and to the plasma membrane is mediated by generated by the phosphorylation of by phosphoinositide 3-OH kinase growth and of PKB/Akt is inhibited by of and D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar, EMBO J. PubMed Scopus Google T.F. Datta K. A. D.R. Tsichlis P.N. PubMed Scopus Google Scholar). growth factor of PI3K are to PKB/Akt P.J. PubMed Scopus Google Scholar). Moreover, the growth of and this effect is by Coadwell J. Stephens L.R. Hawkins P.T. Curr. Biol. 1998; 8: PubMed Scopus Google Scholar). results that PI3K can as of PKB/Akt and can the of to PKB/Akt is a kinase of a and a and is capable of a of B. Biochem. Sci. 1997; PubMed Scopus Google Scholar, A. 1997; PubMed Scopus Google Scholar, P. A. D. P. A. J. 1997; PubMed Scopus Google Scholar). PI3K is activated by the of the with activated growth factor PubMed Scopus Google Scholar). The of PI3K to signaling to the of to the plasma membrane and the of the The activated at the of the the the of PKB/Akt and to the plasma growth and been shown to be of and in this effect is mediated by the of PKB/Akt Science. PubMed Scopus Google Scholar, D. D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, A. Tsichlis P.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, A. Biol. 1997; PubMed Scopus Google Scholar, J. A. Tsichlis P.N. N. 1997; PubMed Scopus Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar). is a well of the PI3K-PKB/Akt signaling pathway (4Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2495) Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar, Biol. 1996; PubMed Scopus Google Scholar). apoptosis in and apoptosis in cells in to growth factor A. Biol. 1997; PubMed Scopus Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar). In both protection from apoptosis is by of PI3K or by PKB/Akt Moreover, constitutively active PI3K or PKB/Akt the of the PI3K-PKB/Akt signaling pathway by with the of PI3K P. A. D. P. A. J. 1997; PubMed Scopus Google Scholar). of the PI3K-PKB/Akt signaling pathway protection from apoptosis in in to and cells from apoptosis induced by J. A. Tsichlis P.N. N. 1997; PubMed Scopus Google Scholar, A. P. P. J. 1997; PubMed Scopus Google Scholar, A. P. S. J. EMBO J. 1997; PubMed Scopus Google Scholar). In this to the of to as p53 tumor suppressor protein is a factor capable of growth or apoptosis M. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). In to DNA p53 a cell by the expression of the This cells to DNA T. D. B. 1993; PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar). in to growth factor p53 can apoptosis. p53-mediated apoptosis in cell a p53. In this the and been shown to be capable of apoptosis. The of p53-mediated apoptosis in the at a tumor to the of and this is to be a p53 is in is a of p53-mediated apoptosis in cells S. Biol. 15: PubMed Scopus Google Scholar). In addition, the of kinase is to cells from p53-mediated apoptosis in to J. J. D. 1998; PubMed Scopus Google Scholar). is a well of the PI3K-PKB/Akt pathway D. D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). Moreover, p53-mediated apoptosis in baby rat kidney cell by and is is by Biol. 15: PubMed Scopus Google Scholar). that p53-mediated apoptosis is in the PI3K-PKB/Akt pathway is of was of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. this we a well cell in apoptosis is P. J. PubMed Scopus Google Scholar, D. P. Oncogene. 1997; 15: PubMed Scopus Google Scholar, L. Biol. PubMed Scopus Google Scholar, M. 1993; 7: PubMed Scopus Google Scholar). this cell we demonstrate that both constitutively active PI3K and PKB/Akt the onset of p53-mediated apoptosis. Moreover, we that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. results provide the first unambiguous and that the PI3K-PKB/Akt pathway can from apoptosis induced by the p53 tumor suppressor demonstrate in this report that both PI3K and PKB/Akt are capable of the onset of apoptosis induced by the tumor suppressor protein p53. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. The protection from p53-mediated apoptosis by PI3K and PKB/Akt was as both the and cell to cell death at the this the by apoptosis is apoptosis in cell by and is and is by a of as P. J. 1997; 8: Google Scholar, L. D. J. Biol. 1996; PubMed Scopus Google Scholar). are a of that apoptosis by and cellular in cell 1996; PubMed Scopus Google Scholar). in cells results from the of in a with at the of the and J. 1998; PubMed Scopus Google Scholar, Science. 1998; PubMed Scopus Google Scholar). is that activated by the of from in to in N. Oncogene. 1998; PubMed Scopus Google Scholar). that PKB/Akt can and and apoptosis N. Franke T.F. S. Science. 1998; PubMed Scopus Google Scholar). in cell PKB/Akt apoptosis the direct of active PKB/Akt was capable of the of p53-mediated was of conferring protection at is to that the of apoptosis are by as that are by in p53-mediated apoptosis is by the that can apoptosis induced by and J. Biol. PubMed Scopus Google Scholar, J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). Moreover, a that the of can p53 in the of by H. Science. PubMed Scopus Google Scholar). to determine if is activated at the in cell by and are in pro-apoptotic protein the of and by and J. H. J. 1996; PubMed Scopus Google Scholar). has been shown to be a of and the phosphorylation of by PKB/Akt from with and J. H. J. 1996; PubMed Scopus Google Scholar, L. M. Science. 1997; PubMed Scopus Google Scholar, H. S. H. M.E. 1997; PubMed Scopus Google Scholar). with and are capable of apoptosis the of Oncogene. 1998; PubMed Scopus Google Scholar, J. H. J. 1996; PubMed Scopus Google Scholar). is a of p53 in cell by and and expression is to apoptosis J. P. D. L. D. 1996; PubMed Scopus Google Scholar). by and the of and with PKB/Akt from apoptosis induced by p53. expression was in the cell at both and the onset of p53-mediated apoptosis in the be by the phosphorylation of This is as has a of expression S. M. D. A. S. J. 1998; Google Scholar). Moreover, the of cells is by the of PKB/Akt in the absence of phosphorylation Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). PKB/Akt to to from apoptosis induced by or p53. The that PKB/Akt the onset of apoptosis by be at this that PI3K and PKB/Akt can cell by the kinetics of apoptosis induced by p53. It therefore be of interest to determine if can the of that by apoptosis. p53 has been shown to mediate apoptosis in to and T. 1993; PubMed Scopus Google Scholar, 1993; PubMed Scopus Google Scholar, J. D. K. 1993; Google Scholar, B.A. T. 1993; PubMed Scopus Google Scholar, J. L. 1993; Google Scholar). This be in the of as in the PI3K-PKB/Akt pathway has been shown to be activated J.Q. A. Taguchi T. Franke T.F. Tsichlis P.N. Testa J.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, L. T. D. B. PubMed Scopus Google Scholar, H. M. H. D. Google of p53-mediated apoptosis in tumor N. 8: PubMed Scopus Google Scholar, H. 8: PubMed Scopus Google Scholar, T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the of p53 is in tumor as is to be a event in 1997; PubMed Scopus Google Scholar). that to the of p53-mediated apoptosis at the of The of to is with a of and p53 the from to growth A. P.J. B.A. Google Scholar). In the of the B. PubMed Scopus Google Scholar). is that of the PI3K-PKB/Akt pathway to the of apoptosis induced by p53 the of in the of tumor growth p53-mediated apoptosis is by is capable of p53-mediated apoptosis in cell by and and the PI3K-PKB/Akt pathway is of signaling activated of Biol. 15: PubMed Scopus Google Scholar, P. B. J. PubMed Scopus Google Scholar, P.R. J. 1993; PubMed Scopus Google Scholar, J. J. 1993; PubMed Scopus Google Scholar, A.B. 1993; PubMed Scopus Google Scholar, A. Biol. PubMed Scopus Google Scholar, M. J.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). It be to determine signaling protection from apoptosis induced by as this to as in The serine/threonine protein kinase PKB/Akt was originally identified as the cellular counterpart of the v-Akt transforming protein present in AKT8, a retrovirus that causes T cell lymphomas in mice (1Staal S.P. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 5034-5037Crossref PubMed Scopus (635) Google Scholar). v-Akt was generated by a fusion event that juxtaposes the retroviral glycosaminoglycan protein and the entire coding region of PKB/Akt (2Coffer P.J. Jin J. Woodgett J.R. Biochem. J. 1998; 335: 1-13Crossref PubMed Scopus (966) Google Scholar, 3Bellacosa A. Franke T.F. Gonzalez-Portal M.E. Datta K. Taguchi T. Gardner J. Cheng J.Q. Testa J.R. Tsichlis P.N. Oncogene. 1993; 8: 745-754PubMed Google Scholar). The fusion protein, designated glycosaminoglycan-PKB, is constitutively active due to a myristoylation signal present within the amino terminus of the glycosaminoglycan protein that targets PKB/Akt to the plasma In quiescent or serum-starved cells, PKB/Akt resides within the cytosol in a catalytically inactive state. Upon stimulation of cells with growth factors and cytokines, PKB/Akt is recruited to the plasma membrane and catalytically activated by phosphorylation at threonine 308 and serine 473 (4Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2495) Google Scholar, 5Stokoe D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar, 6Stephens L. Anderson K. Stokoe D. Erdjument-Bromage H. Painter G.F. Holmes A.B. Gaffney P.R. Reese C.B. McCormick F. Tempst P. Coadwell J. Hawkins P.T. Science. 1998; 279: 710-714Crossref PubMed Scopus (910) Google Scholar, 7Alessi D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar, F. J. Biol. 1996; PubMed Scopus Google Scholar). of PKB/Akt at threonine 308 is by the and constitutively active protein kinase D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar, 7Alessi D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar). The kinase phosphorylation of PKB/Akt at serine 473 has been been M. L. Woodgett J. S. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). of both PKB/Akt and to the plasma membrane is mediated by generated by the phosphorylation of by phosphoinositide 3-OH kinase growth and of PKB/Akt is inhibited by of and D.R. Deak M. Casamayor A. Caudwell F.B. Morrice N. Norman D.G. Gaffney P. Reese C.B. MacDougall C.N. Harbison D. Ashworth A. Bownes M. Curr. Biol. 1997; 7: 776-789Abstract PubMed Scopus Google Scholar, EMBO J. PubMed Scopus Google T.F. Datta K. A. D.R. Tsichlis P.N. PubMed Scopus Google Scholar). growth factor of PI3K are to PKB/Akt P.J. PubMed Scopus Google Scholar). Moreover, the growth of and this effect is by Coadwell J. Stephens L.R. Hawkins P.T. Curr. Biol. 1998; 8: PubMed Scopus Google Scholar). results that PI3K can as of PKB/Akt and can the of to PKB/Akt PI3K is a kinase of a and a and is capable of a of B. Biochem. Sci. 1997; PubMed Scopus Google Scholar, A. 1997; PubMed Scopus Google Scholar, P. A. D. P. A. J. 1997; PubMed Scopus Google Scholar). PI3K is activated by the of the with activated growth factor PubMed Scopus Google Scholar). The of PI3K to signaling to the of to the plasma membrane and the of the The activated at the of the the the of PKB/Akt and to the plasma growth and been shown to be of and in this effect is mediated by the of PKB/Akt Science. PubMed Scopus Google Scholar, D. D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, A. Tsichlis P.N. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, A. Biol. 1997; PubMed Scopus Google Scholar, J. A. Tsichlis P.N. N. 1997; PubMed Scopus Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar). is a well of the PI3K-PKB/Akt signaling pathway (4Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2495) Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar, Biol. 1996; PubMed Scopus Google Scholar). apoptosis in and apoptosis in cells in to growth factor A. Biol. 1997; PubMed Scopus Google Scholar, H. Datta Franke T.F. D.R. M.E. Science. 1997; PubMed Scopus Google Scholar). In both protection from apoptosis is by of PI3K or by PKB/Akt Moreover, constitutively active PI3K or PKB/Akt the of the PI3K-PKB/Akt signaling pathway by with the of PI3K P. A. D. P. A. J. 1997; PubMed Scopus Google Scholar). of the PI3K-PKB/Akt signaling pathway protection from apoptosis in in to and cells from apoptosis induced by J. A. Tsichlis P.N. N. 1997; PubMed Scopus Google Scholar, A. P. P. J. 1997; PubMed Scopus Google Scholar, A. P. S. J. EMBO J. 1997; PubMed Scopus Google Scholar). In this to the of to as The p53 tumor suppressor protein is a factor capable of growth or apoptosis M. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). In to DNA p53 a cell by the expression of the This cells to DNA T. D. B. 1993; PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar). in to growth factor p53 can apoptosis. p53-mediated apoptosis in cell a p53. In this the and been shown to be capable of apoptosis. The of p53-mediated apoptosis in the at a tumor to the of and this is to be a p53 is in The is a of p53-mediated apoptosis in cells S. Biol. 15: PubMed Scopus Google Scholar). In addition, the of kinase is to cells from p53-mediated apoptosis in to J. J. D. 1998; PubMed Scopus Google Scholar). is a well of the PI3K-PKB/Akt pathway D. D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). Moreover, p53-mediated apoptosis in baby rat kidney cell by and is is by Biol. 15: PubMed Scopus Google Scholar). that p53-mediated apoptosis is in the PI3K-PKB/Akt pathway is In of was of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. this we a well cell in apoptosis is P. J. PubMed Scopus Google Scholar, D. P. Oncogene. 1997; 15: PubMed Scopus Google Scholar, L. Biol. PubMed Scopus Google Scholar, M. 1993; 7: PubMed Scopus Google Scholar). this cell we demonstrate that both constitutively active PI3K and PKB/Akt the onset of p53-mediated apoptosis. Moreover, we that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. results provide the first unambiguous and that the PI3K-PKB/Akt pathway can from apoptosis induced by the p53 tumor suppressor demonstrate in this report that both PI3K and PKB/Akt are capable of the onset of apoptosis induced by the tumor suppressor protein p53. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. The protection from p53-mediated apoptosis by PI3K and PKB/Akt was as both the and cell to cell death at the this the by apoptosis is apoptosis in cell by and is and is by a of as P. J. 1997; 8: Google Scholar, L. D. J. Biol. 1996; PubMed Scopus Google Scholar). are a of that apoptosis by and cellular in cell 1996; PubMed Scopus Google Scholar). in cells results from the of in a with at the of the and J. 1998; PubMed Scopus Google Scholar, Science. 1998; PubMed Scopus Google Scholar). is that activated by the of from in to in N. Oncogene. 1998; PubMed Scopus Google Scholar). that PKB/Akt can and and apoptosis N. Franke T.F. S. Science. 1998; PubMed Scopus Google Scholar). in cell PKB/Akt apoptosis the direct of active PKB/Akt was capable of the of p53-mediated was of conferring protection at is to that the of apoptosis are by as that are by in p53-mediated apoptosis is by the that can apoptosis induced by and J. Biol. PubMed Scopus Google Scholar, J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). Moreover, a that the of can p53 in the of by H. Science. PubMed Scopus Google Scholar). to determine if is activated at the in cell by and are in pro-apoptotic protein the of and by and J. H. J. 1996; PubMed Scopus Google Scholar). has been shown to be a of and the phosphorylation of by PKB/Akt from with and J. H. J. 1996; PubMed Scopus Google Scholar, L. M. Science. 1997; PubMed Scopus Google Scholar, H. S. H. M.E. 1997; PubMed Scopus Google Scholar). with and are capable of apoptosis the of Oncogene. 1998; PubMed Scopus Google Scholar, J. H. J. 1996; PubMed Scopus Google Scholar). is a of p53 in cell by and and expression is to apoptosis J. P. D. L. D. 1996; PubMed Scopus Google Scholar). by and the of and with PKB/Akt from apoptosis induced by p53. expression was in the cell at both and the onset of p53-mediated apoptosis in the be by the phosphorylation of This is as has a of expression S. M. D. A. S. J. 1998; Google Scholar). Moreover, the of cells is by the of PKB/Akt in the absence of phosphorylation Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). PKB/Akt to to from apoptosis induced by or p53. The that PKB/Akt the onset of apoptosis by be at this that PI3K and PKB/Akt can cell by the kinetics of apoptosis induced by p53. It therefore be of interest to determine if can the of that by apoptosis. p53 has been shown to mediate apoptosis in to and T. 1993; PubMed Scopus Google Scholar, 1993; PubMed Scopus Google Scholar, J. D. K. 1993; Google Scholar, B.A. T. 1993; PubMed Scopus Google Scholar, J. L. 1993; Google Scholar). This be in the of as in the PI3K-PKB/Akt pathway has been shown to be activated J.Q. A. Taguchi T. Franke T.F. Tsichlis P.N. Testa J.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, L. T. D. B. PubMed Scopus Google Scholar, H. M. H. D. Google of p53-mediated apoptosis in tumor N. 8: PubMed Scopus Google Scholar, H. 8: PubMed Scopus Google Scholar, T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the of p53 is in tumor as is to be a event in 1997; PubMed Scopus Google Scholar). that to the of p53-mediated apoptosis at the of The of to is with a of and p53 the from to growth A. P.J. B.A. Google Scholar). In the of the B. PubMed Scopus Google Scholar). is that of the PI3K-PKB/Akt pathway to the of apoptosis induced by p53 the of in the of tumor growth p53-mediated apoptosis is by is capable of p53-mediated apoptosis in cell by and and the PI3K-PKB/Akt pathway is of signaling activated of Biol. 15: PubMed Scopus Google Scholar, P. B. J. PubMed Scopus Google Scholar, P.R. J. 1993; PubMed Scopus Google Scholar, J. J. 1993; PubMed Scopus Google Scholar, A.B. 1993; PubMed Scopus Google Scholar, A. Biol. PubMed Scopus Google Scholar, M. J.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). It be to determine signaling protection from apoptosis induced by as this to as in We demonstrate in this report that both PI3K and PKB/Akt are capable of the onset of apoptosis induced by the tumor suppressor protein p53. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. The protection from p53-mediated apoptosis by PI3K and PKB/Akt was as both the and cell to cell death at the this the by apoptosis is p53-mediated apoptosis in cell by and is and is by a of as P. J. 1997; 8: Google Scholar, L. D. J. Biol. 1996; PubMed Scopus Google Scholar). are a of that apoptosis by and cellular in cell 1996; PubMed Scopus Google Scholar). in cells results from the of in a with at the of the and J. 1998; PubMed Scopus Google Scholar, Science. 1998; PubMed Scopus Google Scholar). is that activated by the of from in to in N. 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