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• W2053185662 abstract "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)ethyl]glycine 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 Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 8Kohn A.D. Takeuchi F. Roth R.A. J. Biol. Chem. 1996; 271: 21920-21926Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). Phosphorylation of PKB/Akt at threonine 308 is catalyzed by the ubiquitously expressed and constitutively active protein kinase PDK-1 (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, 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 Full Text Full Text PDF PubMed Scopus (616) Google Scholar). The kinase responsible for phosphorylation of PKB/Akt at serine 473 has not been definitively established, although possible candidates have been proposed (9Delcommenne M. Tan C. Gray V. Rue L. Woodgett J. Dedhar S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11211-11216Crossref PubMed Scopus (941) Google Scholar). Recruitment of both PKB/Akt and PDK-1 to the plasma membrane is mediated by second messenger phosphorylated phosphoinositides generated by the phosphorylation of inositol lipids by phosphoinositide 3-OH kinase (PI3K).1 Platelet-derived growth factor- and IGF-mediated activation of PKB/Akt is inhibited by two pharmacological inhibitors of PI3K, LY294002 and wortmannin (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 Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 10Kohn A.D. Kovacina K.S. Roth R.A. EMBO J. 1995; 14: 4288-4295Crossref PubMed Scopus (318) Google Scholar,11Franke T.F. Yang S.I. Chan T.O. Datta K. Kazlauskas A. Morrison D.K. Kaplan D.R. Tsichlis P.N. Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1820) Google Scholar). Also, platelet-derived growth factor receptor mutants incapable of activating PI3K are likewise unable to activate PKB/Akt (12Burgering B.M. Coffer P.J. Nature. 1995; 376: 599-602Crossref PubMed Scopus (1872) Google Scholar). Moreover, PDK-1 potentiates the platelet-derived growth factor-mediated activation of PKB/Akt, and this effect is abrogated by wortmannin (13Anderson K.E. Coadwell J. Stephens L.R. Hawkins P.T. Curr. Biol. 1998; 8: 684-691Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). Taken together, these results indicate that PI3K can function as an upstream activator of PKB/Akt and can regulate the ability of PDK-1 to modulate PKB/Akt activityPI3K is a heterodimeric lipid kinase consisting of a p85 regulatory subunit and a p110 catalytic subunit and is capable of triggering a plethora of biological responses (14Vanhaesebroeck B. Leevers S.J. Panayotou G. Waterfield M.D. Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (827) Google Scholar, 15Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar, 16Rodriguez-Viciana P. Warne P.H. Khwaja A. Marte B.M. Pappin D. Das P. Waterfield M.D. Ridley A. Downward J. Cell. 1997; 89: 457-467Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar). PI3K is activated by the interaction of the p85 regulatory subunit with phosphorylated tyrosine residues on activated growth factor receptors (17Heldin C.H. Cell. 1995; 80: 213-223Abstract Full Text PDF PubMed Scopus (1427) Google Scholar). The binding of PI3K to upstream signaling molecules leads to the recruitment of p85-p110 heterodimeric complexes to the plasma membrane and the subsequent activation of the p110 catalytic subunit. The activated p110 catalytic subunit phosphorylates inositol lipids at the 3-position of the inositol ring, thereby generating the phospholipid second messenger molecules required for the transposition of PKB/Akt and PDK-1 to the plasma membrane.Cytokines, growth factors, and certain oncogenes have been shown to be effective inhibitors of apoptosis, and in many situations, this anti-apoptotic effect is mediated by the PI3K-induced activation of PKB/Akt (18Yao R. Cooper G.M. Science. 1995; 267: 2003-2006Crossref PubMed Scopus (1288) Google Scholar, 19Songyang Z. Baltimore D. Cantley L.C. Kaplan D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11345-11350Crossref PubMed Scopus (322) Google Scholar, 20Ahmed N.N. Grimes H.L. Bellacosa A. Chan T.O. Tsichlis P.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3627-3632Crossref PubMed Scopus (486) Google Scholar, 21Kulik G. Klippel A. Weber M.J. Mol. Cell. Biol. 1997; 17: 1595-1606Crossref PubMed Scopus (964) Google Scholar, 22Kennedy S.G. Wagner A.J. Conzen S.D. Jordan J. Bellacosa A. Tsichlis P.N. Hay N. Genes Dev. 1997; 11: 701-713Crossref PubMed Scopus (977) Google Scholar, 23Dudek 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 (2213) Google Scholar). IGF-1 is a well documented activator 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, 23Dudek 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 (2213) Google Scholar, 24Mendez R. Myers Jr., M.G. White M.F. Rhoads R.E. Mol. Cell. Biol. 1996; 16: 2857-2864Crossref PubMed Scopus (205) Google Scholar). IGF-1 inhibits UV-induced apoptosis in fibroblasts and prevents apoptosis in neuronal cells in response to growth factor withdrawal (21Kulik G. Klippel A. Weber M.J. Mol. Cell. Biol. 1997; 17: 1595-1606Crossref PubMed Scopus (964) Google Scholar, 23Dudek 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 (2213) Google Scholar). In both cases, IGF-1-mediated protection from apoptosis is abrogated either by pharmacological inhibitors of PI3K or by dominant-negative PKB/Akt constructs. Moreover, constitutively active PI3K or PKB/Akt mimics the anti-apoptotic function of IGF-1. Ras activates the PI3K-PKB/Akt signaling pathway by interacting directly with the p110 catalytic subunit of PI3K (16Rodriguez-Viciana P. Warne P.H. Khwaja A. Marte B.M. Pappin D. Das P. Waterfield M.D. Ridley A. Downward J. Cell. 1997; 89: 457-467Abstract Full Text Full Text PDF PubMed Scopus (954) Google Scholar). Ras-induced activation of the PI3K-PKB/Akt signaling pathway confers protection from apoptosis in fibroblasts in response to oncogenic Myc and protects epithelial cells from apoptosis induced by anoikis (22Kennedy S.G. Wagner A.J. Conzen S.D. Jordan J. Bellacosa A. Tsichlis P.N. Hay N. Genes Dev. 1997; 11: 701-713Crossref PubMed Scopus (977) Google Scholar, 25Kauffmann-Zeh A. Rodriguez-Viciana P. Ulrich E. Gilbert C. Coffer P. Downward J. Evan G. Nature. 1997; 385: 544-548Crossref PubMed Scopus (1069) Google Scholar, 26Khwaja A. Rodriguez-Viciana P. Wennstrom S. Warne P.H. Downward J. EMBO J. 1997; 16: 2783-2793Crossref PubMed Scopus (932) Google Scholar). In this respect, PI3K-PKB/Akt-mediated survival contributes to the ability of Ras to function as an oncogene.The p53 tumor suppressor protein is a transcription factor capable of inducing either growth arrest or apoptosis (27Gottlieb T.M. Oren M. Biochim. Biophys. Acta. 1996; 1287: 77-102Crossref PubMed Scopus (509) Google Scholar, 28Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6698) Google Scholar, 29Lane D.P. Nature. 1992; 358: 15-16Crossref PubMed Scopus (4436) Google Scholar). In response to DNA damage, p53 induces a G1-specific cell cycle arrest by transcriptionally up-regulating the expression of the cyclin/Cdk inhibitor, p21/WAF-1-Cip1. This allows cells time to repair damaged DNA before progressing into S phase (30el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7890) Google Scholar, 31Hartwell L.H. Kastan M.B. Science. 1994; 266: 1821-1828Crossref PubMed Scopus (2303) Google Scholar). However, in response to oncogenic activation and/or growth factor withdrawal, p53 can induce apoptosis. p53-mediated apoptosis in certain cell types requires a transcriptionally functional p53. In this respect, the p53-inducible proteins Bax and IGF-binding protein-3 have been shown to be capable of inducing apoptosis. The inhibition of p53-mediated apoptosis in vivo potentiates the rate at which a tumor progresses to the stage of malignancy, and this is thought to be a major reason why p53 is so often mutated in human cancers.The cytokine IL-3 is a potent inhibitor of p53-mediated apoptosis in erythroleukemia cells (32Lin Y. Benchimol S. Mol. Cell. Biol. 1995; 15: 6045-6054Crossref PubMed Scopus (76) Google Scholar). In addition, the IL-3-mediated activation of JAK kinase is sufficient to protect myeloid cells from p53-mediated apoptosis in response to γ-radiation (33Quelle F.W. Wang J. Feng J. Wang D. Cleveland J.L. Ihle J.N. Zambetti G.P. Genes Dev. 1998; 12: 1099-1107Crossref PubMed Scopus (94) Google Scholar). IL-3 is also a well established activator of the PI3K-PKB/Akt survival pathway (19Songyang Z. Baltimore D. Cantley L.C. Kaplan D.R. Franke T.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11345-11350Crossref PubMed Scopus (322) Google Scholar). Moreover, p53-mediated apoptosis in baby rat kidney (BRK) cell lines transformed by E1A and tsp53(Val-135) (where ts is temperature-sensitive) is suppressed by oncogenic Ras (34Lin H.J. Eviner V. Prendergast G.C. White E. Mol. Cell. Biol. 1995; 15: 4536-4544Crossref PubMed Scopus (104) Google Scholar). These findings indicate that p53-mediated apoptosis is inhibitable under conditions in which the PI3K-PKB/Akt survival pathway is activated.In light of these findings, it was of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. To this end, we employed a well characterized cell culture system in which apoptosis is exclusively p53-dependent (35Sabbatini P. Lin J. Levine A.J. White E. Genes Dev. 1995; 9: 2184-2192Crossref PubMed Scopus (227) Google Scholar, 36Sakamuro D. Sabbatini P. White E. Prendergast G.C. Oncogene. 1997; 15: 887-898Crossref PubMed Scopus (249) Google Scholar, 37Chiou S.K. Rao L. White E. Mol. Cell. Biol. 1994; 14: 2556-2563Crossref PubMed Scopus (361) Google Scholar, 38Debbas M. White E. Genes Dev. 1993; 7: 546-554Crossref PubMed Scopus (831) Google Scholar). Using this cell culture system, we demonstrate that both constitutively active PI3K and PKB/Akt compromise the onset of p53-mediated apoptosis. Moreover, we find that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. These results provide the first unambiguous and compelling evidence that the PI3K-PKB/Akt survival pathway can protect from apoptosis induced by the p53 tumor suppressor protein.DISCUSSIONWe demonstrate in this report that both PI3K and PKB/Akt are capable of compromising the onset of apoptosis induced exclusively by the tumor suppressor protein p53. This was manifested as a significant 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 conferred by PI3K and PKB/Akt was not permanent, as both the Akt-1 and 110-1 cell lines ultimately succumbed to cell death at the permissive temperature. One possible explanation for this observation centers around the mechanism by which p53-mediated, transcriptionally dependent apoptosis is induced.p53-mediated apoptosis in BRK cell lines transformed by E1A and tsp53(Val-135) is transcriptionally dependent and is triggered by a class of enzymes known as caspases (44Sabbatini P. Han J. Chiou S.K. Nicholson D.W. White E. Cell Growth Differ. 1997; 8: 643-653PubMed Google Scholar, 46Rao L. Perez D. White E. J. Cell Biol. 1996; 135: 1441-1455Crossref PubMed Scopus (510) Google Scholar). Caspases are a family of aspartate-specific proteases that induce apoptosis by cleaving and inactivating cellular substrates, which play an essential role in maintaining cell viability (47Nicholson D.W. Nat. Biotechnol. 1996; 14: 297-301Crossref PubMed Scopus (239) Google Scholar). Apoptosis in mammalian cells results from the activation of caspases in a cascade-like fashion, with initiator caspases lying at the apex of the cascade and effector caspases lying farther downstream (48Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Crossref PubMed Scopus (1160) Google Scholar, 49Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Crossref PubMed Scopus (6133) Google Scholar). Caspase-9 is an initiator caspase that becomes activated by the release of cytochrome c from mitochondria in response to many apoptotic stimuli (reviewed in Ref. 50Nunez G. Benedict M.A. Hu Y. Inohara N. Oncogene. 1998; 17: 3237-3245Crossref PubMed Scopus (944) Google Scholar). Recent evidence indicates that PKB/Akt can phosphorylate and inactivate caspase-9 and thereby abrogate caspase-9-mediated apoptosis (51Cardone M.H. Roy N. Stennicke H.R. Salvesen G.S. Franke T.F. Stanbridge E. Frisch S. Reed J.C. Science. 1998; 282: 1318-1321Crossref PubMed Scopus (2719) Google Scholar). Thus, in certain cell types, PKB/Akt may abrogate apoptosis through the direct inhibition of caspases. Constitutively active PKB/Akt was capable of abrogating the early stages of p53-mediated apoptosis, but was incapable of conferring protection at later time points (Fig. 2). Therefore, it is tempting to speculate that the early stages of p53-mediated, transcriptionally dependent apoptosis are triggered by initiator caspases such as caspase-9 that are inhibitable by PKB/Akt. A role for capsase-9 in p53-mediated apoptosis per se is implicated by the observation that dominant-negative caspase-9 constructs can inhibit apoptosis induced by E1A and Bax (52Seol D.-W. Billiar T.R. J. Biol. Chem. 1999; 274: 2072-2076Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 53Fearnhead H.O. Rodriguez J. Govek E.E. Guo W. Kobayashi R. Hannon G. Lazebnik Y.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13664-13669Crossref PubMed Scopus (159) Google Scholar). Moreover, a recent study indicates that the inactivation of caspase-9 can substitute for p53 loss in permitting the oncogenic transformation of primary mouse embryo fibroblasts by c-Myc (54Soengas M.S. Alarcón R.M. Yoshida H. Giaccia A.J. Hakem R. Mak T.W. Lowe S.W. Science. 1999; 284: 156-159Crossref PubMed Scopus (594) Google Scholar). Experiments to determine if caspase-9 is activated at the permissive temperature in BRK cell lines transformed by E1A and tsp53(Val-135) are in progress.The pro-apoptotic protein Bad antagonizes the anti-apoptotic function of Bcl-2 and Bcl-Xl by forming inactivating Bad-Bcl-2 and Bad-Bcl-Xl heterodimers (55Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Bad has recently been shown to be a target of PKB/Akt-mediated phosphorylation, and the phosphorylation of Bad by PKB/Akt prevents Bad from heterodimerizing with Bcl-2 and Bcl-Xl (55Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar, 56del Peso L. Gonzalez-Garcia M. Page C. Herrera R. Nunez G. Science. 1997; 278: 687-689Crossref PubMed Scopus (1978) Google Scholar, 57Datta S.R. Dudek H. Tao X. Masters S. Fu H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4915) Google Scholar). When uncomplexed with Bad, Bcl-2 and Bcl-Xl are capable of abrogating Bax-mediated apoptosis through the formation of Bcl-2/Bcl-Xl-Bax heterodimers (42Reed J.C. Oncogene. 1998; 17: 3225-3236Crossref PubMed Scopus (936) Google Scholar, 55Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Bax is a transcriptional target of p53 in BRK cell lines transformed by E1A and tsp53(Val-135), and its expression is sufficient to induce apoptosis (40Han J. Sabbatini P. Perez D. Rao L. Modha D. White E. Genes Dev. 1996; 10: 461-477Crossref PubMed Scopus (313) Google Scholar). Therefore, by phosphorylating Bad and potentiating the interaction of Bcl-2 and Bcl-Xl with Bax, PKB/Akt could conceivably protect from apoptosis induced by p53. However, Bad expression was completely undetectable in the Akt-1 cell line at both 38.5 and 32 °C (data not shown). Therefore, the delayed onset of p53-mediated apoptosis observed in the Akt-1 line cannot be explained by the PKB/Akt-mediated phosphorylation of Bad. This result is not unexpected, as Bad has a very restricted pattern of tissue expression (58Kitada S. Krajewska M. Zhang X. Scudiero D. Zapata J.M. Wang H.G. Shabaik A. Tudor G. Krajewski S. Myers T.G. Johnson G.S. Sausville E.A. Reed J.C. Am. J. Pathol. 1998; 152: 51-61PubMed Google Scholar). Moreover, the IL-4-mediated survival of myeloid cells is paralleled by the activation of PKB/Akt in the absence of Bad phosphorylation (59Scheid M.P. Duronio V. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7439-7444Crossref PubMed Scopus (276) Google Scholar). Thus, PKB/Akt does not need to phosphorylate Bad to protect from apoptosis induced by either IL-4 deprivation or p53. The possibility that PKB/Akt compromises the onset of p53-dependent apoptosis by phosphorylating Bad-like proteins, however, cannot be discounted at this time.We have demonstrated that PI3K and PKB/Akt can promote cell survival by compromising the kinetics of apoptosis induced by p53. It would therefore be of interest to determine if PI3K-PKB/Akt-mediated survival can restrict the efficacy of anticancer interventions that function by triggering p53-induced apoptosis. Indeed, p53 has been shown to mediate apoptosis in response to γ-radiation and certain chemotherapeutic reagents (60Lowe S.W. Ruley H.E. Jacks T. Housman D.E. Cell. 1993; 74: 957-967Abstract Full Text PDF PubMed Scopus (2951) Google Scholar, 61Clarke A.R. Purdie C.A. Harrison D.J. Morris R.G. Bird C.C. Hooper M.L. Wyllie A.H. 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Ma Y.Y. Carcangiu M.L. Pinkel D. Yang-Feng T.L. Gray J.W. Cancer Res. 1995; 55: 6172-6180PubMed Google Scholar).The abrogation of p53-mediated apoptosis through inactivating mutations represents an important driving force in tumor development (68Howes K.A. Ransom N. Papermaster D.S. Lasudry J.G. Albert D.M. Windle J.J. Genes Dev. 1994; 8: 1300-1310Crossref PubMed Scopus (295) Google Scholar, 69Pan H. Griep A.E. Genes Dev. 1994; 8: 1285-1299Crossref PubMed Scopus (383) Google Scholar, 70Lowe S.W. Jacks T. Housman D.E. Ruley H.E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2026-2030Crossref PubMed Scopus (285) Google Scholar). However, the inactivation of p53 is typically not involved in tumor initiation, as it is frequently observed to be a late-onset event in human cancers (71Canman C.E. Kastan M.B. Adv. Pharmacol. 1997; 41: 429-460Crossref PubMed Scopus (55) Google Scholar). Thus, there may exist other oncogenic mechanisms that function to modulate the impact of p53-mediated apoptosis at the early stages of cancer development. The transformation of colorectal epithelium to carcinomas is associated with a progressive inhibition of apoptosis, and p53 inactivation occurs near the transition from benign to malignant growth (72Bedi A. Pasricha P.J. Akhtar A.J. Barber J.P. Bedi G.C. Giardiello F.M. Zehnbauer B.A. Hamilton S.R. Jones R.J. Cancer Res. 1995; 55: 1811-1816PubMed Google Scholar). In contrast, Ras mutations occur most often during the early adenomatous stage of the disease (73Fearon E.R. Vogelstein B. Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (9901) Google Scholar). Thus, it is conceivable that Ras-mediated activation of the PI3K-PKB/Akt survival pathway may function to limit the extent of apoptosis induced by p53 during the early premalignant stages of colon cancer. This, in turn, would facilitate the progression of tumor growth until p53-mediated apoptosis is completely abrogated by inactivating mutations. Ras is capable of suppressing p53-mediated apoptosis in BRK cell lines transformed by E1A and tsp53(Val-135), and the PI3K-PKB/Akt survival pathway is one of many signaling pathways activated downstream of Ras (34Lin H.J. Eviner V. Prendergast G.C. White E. Mol. Cell. Biol. 1995; 15: 4536-4544Crossref PubMed Scopus (104) Google Scholar, 74Rodriguez-Viciana P. Warne P.H. Dhand R. Vanhaesebroeck B. Gout I. Fry M.J. Waterfield M.D. Downward J. Nature. 1994; 370: 527-532Crossref PubMed Scopus (1717) Google Scholar, 75Warne P.H. Viciana P.R. Downward J. Nature. 1993; 364: 352-355Crossref PubMed Scopus (581) Google Scholar, 76Zhang X.F. Settleman J. Kyriakis J.M. Takeuchi-Suzuki E. Elledge S.J. Marshall M.S. Bruder J.T. Rapp U.R. Avruch J. Nature. 1993; 364: 308-313Crossref PubMed Scopus (684) Google Scholar, 77Vojtek A.B. Hollenberg S.M. 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