Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP)

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Nature

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Duplication of Data;Duplication of/in Image;Falsification/Fabrication of Data;Falsification/Fabrication of Image;Investigation by Company/Institution;Manipulation of Images;

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10/21/2016 0:00

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Abstract

Akt negatively regulates apoptotic pathways at a premitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3β. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo. Phosphorylation of XIAP by Akt protects XIAP from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of XIAP is also inhibited by Akt. Consistent with this, an XIAP mutant introduced into cells which mimics the Akt-phosphorylated form (i.e. XIAP-S87D) displays reduced ubiquitination and degradation as compared with wild type XIAP. The greater stability of XIAP-S87D in cells translated to increased cell survival after cisplatin treatment. Conversely, a mutant that could not be phosphorylated by Akt (XIAP-S87A) was more rapidly degraded and showed increased cisplatin-induced apoptosis. Furthermore, suppression of XIAP by either siRNA or adenovirus of antisense of XIAP induced programmed cell death and inhibited Akt-stimulated cell survival in ovarian cancer cells. These data identify XIAP as a new downstream target of Akt and a potentially important mediator of the effect of Akt on cell survival. Akt negatively regulates apoptotic pathways at a premitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3β. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo. Phosphorylation of XIAP by Akt protects XIAP from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of XIAP is also inhibited by Akt. Consistent with this, an XIAP mutant introduced into cells which mimics the Akt-phosphorylated form (i.e. XIAP-S87D) displays reduced ubiquitination and degradation as compared with wild type XIAP. The greater stability of XIAP-S87D in cells translated to increased cell survival after cisplatin treatment. Conversely, a mutant that could not be phosphorylated by Akt (XIAP-S87A) was more rapidly degraded and showed increased cisplatin-induced apoptosis. Furthermore, suppression of XIAP by either siRNA or adenovirus of antisense of XIAP induced programmed cell death and inhibited Akt-stimulated cell survival in ovarian cancer cells. These data identify XIAP as a new downstream target of Akt and a potentially important mediator of the effect of Akt on cell survival. Akt, also named protein kinase B (PKB) 1The abbreviations used are: PKBprotein kinase BXIAPX-linked inhibitor of apoptosis proteinIAPinhibitor of apoptosis proteinHAhemagglutininHEKhuman embryonic kidneyGSTglutathione S-transferaseTUNELterminal deoxynucleotidyltransferase-mediated dUTP nick end labelingsiRNAshort interference RNAE3ubiquitin protease ligaseZbenzyloxycarbonylfmkfluoromethyl ketone.1The abbreviations used are: PKBprotein kinase BXIAPX-linked inhibitor of apoptosis proteinIAPinhibitor of apoptosis proteinHAhemagglutininHEKhuman embryonic kidneyGSTglutathione S-transferaseTUNELterminal deoxynucleotidyltransferase-mediated dUTP nick end labelingsiRNAshort interference RNAE3ubiquitin protease ligaseZbenzyloxycarbonylfmkfluoromethyl ketone. or RAC kinase, is a family of phosphatidylinositol 3-OH-kinase-regulated serine/threonine kinase (1Franke 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 (1826) Google Scholar, 2Burgering B.M. Coffer P.J. Nature. 1995; 376: 599-602Crossref PubMed Scopus (1878) Google Scholar, 3Cross D.A. Alessi D.R. Cohen P. Andjelkovich M. Hemmings B.A. Nature. 1995; 378: 785-789Crossref PubMed Scopus (4364) Google Scholar). Three isoforms of Akt have been identified: Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ, all of which are activated by growth factors in a phosphatidylinositol 3-OH-kinase-dependent manner (4Bellacosa A. Testa J.R. Staal S.P. Tsichlis P.N. Science. 1991; 254: 274-277Crossref PubMed Scopus (790) Google Scholar, 5Cheng J.Q. Godwin A.K. Belacosa A. Taguchi T. Franke T.F. Hamilton T.C. Tsichlis P.N. Testa J.R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9267-9271Crossref PubMed Scopus (647) Google Scholar, 6Nakatani K. Sakaue H. Thompson D.A. Weigel R.J. Roth R.A. Biochem. Biophys. Res. Commun. 1999; 257: 906-910Crossref PubMed Scopus (156) Google Scholar). Full activation of the Akts requires their phosphorylation at Thr308 (Akt1), Thr309 (Akt2), or Thr305 (Akt3) in the activation loop and Ser473 (Akt1), Ser474 (Akt2), or Ser472 (Akt3) in the C-terminal activation domain (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). protein kinase B X-linked inhibitor of apoptosis protein inhibitor of apoptosis protein hemagglutinin human embryonic kidney glutathione S-transferase terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling short interference RNA ubiquitin protease ligase benzyloxycarbonyl fluoromethyl ketone. protein kinase B X-linked inhibitor of apoptosis protein inhibitor of apoptosis protein hemagglutinin human embryonic kidney glutathione S-transferase terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling short interference RNA ubiquitin protease ligase benzyloxycarbonyl fluoromethyl ketone. Accumulated evidence shows that Akt and its downstream targets constitute a major cell survival pathway. Akt promotes cell survival and suppresses apoptotic death in a number of cell types induced by a variety of stimuli, including growth factor withdrawal, cell cycle discordance, and loss of cell adhesion (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). Several downstream targets containing the Akt phosphorylation consensus sequence (R-X-R-X-X-S/T) have been identified which shed light on the mechanisms by which Akt promotes cell survival and blocks apoptosis. The first anti-apoptotic Akt target identified was the pro-apoptotic protein BAD. BAD is a pro-death member of the Bcl-2 family that initiates apoptosis by binding to Bcl-xLon the outer mitochondrial membrane, causing the release of cytochrome c into the cytosol. Akt phosphorylates BAD on Ser136, promoting the association of BAD with 14-3-3 proteins in the cytosol and inactivating its proapoptotic function (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). The execution of cellular apoptosis also involves changes in the transcriptional program (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). Akt decreases the transcription of a subset of death genes by phosphorylation of the Forkhead family of transcription factors, which causes their nuclear exclusion and inactivation (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). Akt also phosphorylates and activates the cyclic AMP-response element-binding protein, which increases the transcription of anti-apoptotic genes, such as Bcl-2 (8Du K. Montminy M. J. Biol. Chem. 1998; 273: 32377-32379Abstract Full Text Full Text PDF PubMed Scopus (821) Google Scholar, 9Pugazhenthi S. Nesterova A. Sable C. Heidenreich K.A. Boxer L.M. Heasley L.E. Reusch J.E. J. Biol. Chem. 2000; 275: 10761-10766Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar). In addition, recent studies have shown that Akt phosphorylates and inactivates apoptosis signal-regulating kinase-1, a mitogen-activated protein kinase kinase kinase that mediates stress- and cytokine-induced cell death (10Kim A.H. Khursigara G. Sun X. Franke T.F. Chao M.V. Mol. Cell. Biol. 2001; 21: 893-901Crossref PubMed Scopus (621) Google Scholar, 11Yuan Z. Feldman R.I. Sussman G.E. Coppola D. Nicosia S.V. Cheng J.Q. J. Biol. Chem. 2003; 278: 23432-23440Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). Akt also phosphorylates the murine double minute-2 protein promoting its translocation to the nucleus and the destabilization of p53 (12Zhou B.P. Liao Y. Xia W. Zou Y. Spohn B. Hung M.C. Nat. Cell Biol. 2001; 3: 973-982Crossref PubMed Scopus (785) Google Scholar). By promoting the degradation of p53, Akt impairs the cellular stress response, increasing the survival of tumor cells. A role for an anti-apoptotic function of Akt at a post-mitochondrial step has also been proposed (13Zhou H. Li X.M. Meinkoth J. Pittman R.N. J. Cell Biol. 2000; 151: 483-494Crossref PubMed Scopus (389) Google Scholar), and Akt has been reported to directly phosphorylate and inactivate the cell death protease caspase-9 (14Cardone 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 (2728) Google Scholar). In addition, Akt has also been shown to inhibit the activation of Bax during apoptosis through an uncharacterized mechanism (11Yuan Z. Feldman R.I. Sussman G.E. Coppola D. Nicosia S.V. Cheng J.Q. J. Biol. Chem. 2003; 278: 23432-23440Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 15Yamaguchi H. Wang H.G. Oncogene. 2001; 20: 7779-7786Crossref PubMed Scopus (340) Google Scholar). The inhibitor of apoptosis proteins (IAPs) are a family of intracellular anti-apoptotic proteins, first identified in baculovirus, which play a key role in cell survival by modulating death-signaling pathways at a post-mitochondrial level. They currently include X-linked IAP (XIAP), human IAP-1 (Hiap-1), human IAP-2 (Hiap-2), neuronal apoptosis inhibitory protein (Naip), Survivin, and Livin. These proteins are characterized by the presence of a caspase-recruitment domain and an N-terminal baculovirus-inhibitor-of-apoptosis-repeat motif, which is necessary for biological activity. With the exception of Naip and survivin, IAPs also contain a C-terminal RING-zinc finger domain believed to be involved in protein-protein and protein-nucleic acid interactions (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google Scholar). Recent studies have shown that the RING finger domain has ubiquitin protease ligase (E3) activity and is responsible for the autoubiquitination and degradation of IAPs after an apoptosis stimulus (17Liston P. Roy N. Tamai K. Lefebvre C. Baird S. Cherton-Horvat G. Farahani R. McLean M. Ikeda J.E. MacKenzie A. Korneluk R.G. Nature. 1996; 379: 349-353Crossref PubMed Scopus (870) Google Scholar). Among human IAPs, XIAP is the most potent inhibitor of caspases and apoptosis. It has been shown that XIAP is a direct inhibitor of caspase-3 and caspase-9 and modulates the Bax/cytochrome c pathway by inhibiting caspase-9 (18Deveraux Q.L. Roy N. Stennicke H.R. Van Arsdale T. Zhou Q. Srinivasula S.M. Alnemri E.S. Salvesen G.S. Reed J.C. EMBO J. 1998; 17: 2215-2223Crossref PubMed Scopus (1239) Google Scholar). In the present report, we demonstrate that XIAP is a physiological substrate of Akt. Akt interacts with and phosphorylates XIAP at serine 87. Phosphorylation of XIAP by Akt inhibits both its autoubiquitination and cisplatin-induced ubiquitination. These effects reduce XIAP degradation and the increased levels of XIAP are associated with decreased cisplatin-stimulated caspase 3 activity and programmed cell death. Cell Lines and Transfection—The human ovarian cancer epithelial cell line A2780S and human embryonic kidney (HEK) 293 cells were cultured at 37 °C and 5% CO2 in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum. The cells were transfected with appropriate DNA indicated in the figure legends, using LipofectAMINE Plus (Invitrogen). Plasmid Constructs—Akt plasmids have previously been described (19Sun M. Wang G. Paciga J.E. Feldman R.I. Yuan Z.Q. Ma X.L. Shelley S.A. Jove R. Tsichlis P.N. Nicosia S.V. Cheng J.Q. Am. J. Pathol. 2001; 159: 431-437Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 20Dan H.C. Sun M. Yang L. Feldman R.I. Sui X.M. Ou C.C. Nellist M. Yeung R.S. Halley D.J. Nicosia S.V. Pledger W.J. Cheng J.Q. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). XIAP was by and to and XIAP-S87D mutant were using a ubiquitin and was by and The glutathione S-transferase and were by and to dUTP and cells were with using an in cell death caspase-3 cisplatin cells were and with caspase-3 and in proteins, and were as described previously (19Sun M. Wang G. Paciga J.E. Feldman R.I. Yuan Z.Q. Ma X.L. Shelley S.A. Jove R. Tsichlis P.N. Nicosia S.V. Cheng J.Q. Am. J. Pathol. 2001; 159: 431-437Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 20Dan H.C. Sun M. Yang L. Feldman R.I. Sui X.M. Ou C.C. Nellist M. Yeung R.S. Halley D.J. Nicosia S.V. Pledger W.J. Cheng J.Q. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). in vitro kinase Akt were with a kinase (19Sun M. Wang G. Paciga J.E. Feldman R.I. Yuan Z.Q. Ma X.L. Shelley S.A. Jove R. Tsichlis P.N. Nicosia S.V. Cheng J.Q. Am. J. Pathol. 2001; 159: 431-437Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar). proteins were used as the was In Cell and cells were transfected with with or Akt and with in Eagle's medium for was with The were on and to XIAP was by was as described previously H.C. Sun M. Yang L. Feldman R.I. Sui X.M. Ou C.C. Nellist M. Yeung R.S. Halley D.J. Nicosia S.V. Pledger W.J. Cheng J.Q. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Akt is a of the IAP family and suppresses the programmed cell death by direct of caspase-9 and caspase-3 activity (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google Scholar). of XIAP is an important mechanism for caspase activation in response to apoptotic stimuli, including J.Q. X. M. Li M. H.C. Sun M. 2002; PubMed Scopus Google Scholar). and H. Y. Res. 2000; Google Scholar, T. T. H. H. K. 2001; PubMed Scopus Google have previously shown that cisplatin-induced programmed cell death is by a in XIAP protein also that activation of the Akt pathway cisplatin by of apoptosis Y. S. Science. 2000; PubMed Scopus Google Scholar). to Akt inhibits cisplatin-induced XIAP A2780S ovarian cancer which are to were transfected with or In cisplatin and a of XIAP protein In XIAP levels were in A2780S cells B and showed that also A2780S cells from cisplatin-induced In addition, cisplatin-induced of XIAP is B and Akt effects XIAP at the transcriptional level, we using RNA from or A2780S cells with cisplatin. shown in levels of XIAP were in both cell and not by transcriptional of XIAP by cisplatin and Akt. A is that XIAP and its by cisplatin of cells is a protein degradation we a and cells were with for of was with at and The of XIAP was by and of the shown in XIAP was degraded in the degradation was in the cells These data that Akt promotes increased levels of XIAP in A2780S cells by the protein from the of IAP family are by pathway (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google and of Akt activates S.R. L.M. Nature. 1999; PubMed Scopus Google Scholar, Z.Q. Feldman R.I. Sun M. Coppola D. Sussman G.E. Shelley S.A. Nicosia S.V. Cheng J.Q. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), we Akt XIAP cells were transfected with increasing of Akt. and showed that of Akt not XIAP at protein and levels A and that Akt XIAP is not from of XIAP at level. Recent have that IAP family proteins, including and during the apoptosis R. J. C. Genes Dev. 2003; 17: PubMed Scopus Google Scholar, S.M. S. Datta P. Z. R. N. T. Alnemri E.S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). cisplatin programmed cell death mitochondrial pathway (11Yuan Z. Feldman R.I. Sussman G.E. Coppola D. Nicosia S.V. Cheng J.Q. J. Biol. Chem. 2003; 278: 23432-23440Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, H. Y. Res. 2000; Google Scholar), we the of in cisplatin-induced XIAP A2780S cells were transfected with which is to in response to cisplatin H. N. H. S. T. H. K. S. S. H. Oncogene. 1998; PubMed Scopus Google Scholar). The transfected cells were with cisplatin for and showed that Akt, XIAP from cisplatin-induced at apoptosis A of cisplatin-induced XIAP degradation is either caspase or pathway. A2780S cells were with cisplatin with or caspase inhibitor or inhibitor shown in the XIAP degradation was inhibited by not by These data that the XIAP degradation induced by cisplatin is through pathway. Akt and of has been shown to ubiquitin ligase which is responsible for its autoubiquitination and ubiquitination in response to apoptotic (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google Scholar, J.Q. X. M. Li M. H.C. Sun M. 2002; PubMed Scopus Google Scholar, H. N. H. S. T. H. K. S. S. H. Oncogene. 1998; PubMed Scopus Google Scholar). Akt inhibits autoubiquitination of cells were transfected with ubiquitin with or Akt Consistent with of ubiquitin autoubiquitination of XIAP and its degradation in a manner to inhibitor H. Y. Res. 2000; Google Scholar, H. N. H. S. T. H. K. S. S. H. Oncogene. 1998; PubMed Scopus Google Scholar). of Akt inhibited autoubiquitination of XIAP and degradation of XIAP the effects of Akt on cisplatin-induced XIAP ubiquitination. and A2780S cells were transfected with and with or wild type Akt and with cisplatin. of XIAP was by and after of the treatment. shown in and cisplatin ubiquitination of XIAP that was inhibited by wild type Akt. we that Akt XIAP by of its Akt and with that Akt regulates XIAP at a level that XIAP be a substrate of Akt. protein sequence a consensus Akt phosphorylation sequence at residue serine of which is the baculovirus-inhibitor-of-apoptosis-repeat domain Akt phosphorylates cells were with and and of cells were with for 3 of showed that both and phosphorylation levels of XIAP as compared with cells transfected with XIAP and Akt phosphorylates cells were either transfected with or and with or to XIAP was with and the were to with substrate shown in and induced phosphorylation of of XIAP. The phosphorylation induced by was inhibited by phosphatidylinositol inhibitor that also in to Akt, to phosphorylate XIAP. Akt phosphorylates XIAP at residue of we proteins of wild type XIAP and which was by serine residue into In vitro Akt kinase was using the and proteins as that and phosphorylate wild type XIAP not These data that XIAP is a physiological substrate of Akt A number of Akt have been shown to with Akt, which include and apoptosis signal-regulating (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar, A.H. Khursigara G. Sun X. Franke T.F. Chao M.V. Mol. Cell. Biol. 2001; 21: 893-901Crossref PubMed Scopus (621) Google Scholar, 11Yuan Z. Feldman R.I. Sussman G.E. Coppola D. Nicosia S.V. Cheng J.Q. J. Biol. Chem. 2003; 278: 23432-23440Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). XIAP with Akt. cells were with AKT2, and was with and of the was with or shown in and both and with XIAP. The binding and XIAP is that of and XIAP. Furthermore, an protein-protein XIAP and Akt was also in cells and data not Akt of XIAP on of Akt phosphorylates serine of XIAP and inhibits XIAP ubiquitination and to phosphorylation of XIAP at serine for the effect of Akt on XIAP Akt (XIAP-S87A) and of XIAP were and their of autoubiquitination and cisplatin-induced ubiquitination was in and A2780S shown in and wild type XIAP autoubiquitination the cells were with Furthermore, autoubiquitination levels of XIAP-S87D decreased as compared with and wild type XIAP. wild type XIAP in Akt not effects on either or XIAP-S87D autoubiquitination evidence that phosphorylation of XIAP at serine in and in of XIAP from the of Akt phosphorylation of XIAP on cisplatin-induced ubiquitination and degradation of A2780S cells were transfected with and with cisplatin for we that was in a XIAP-S87D was to cisplatin-induced ubiquitination we also reduced protein levels of not XIAP-S87D in response to cisplatin we that Akt of cisplatin-induced ubiquitination and degradation of XIAP are also in a of Akt Phosphorylation of XIAP on XIAP its anti-apoptotic effects by inhibiting caspase-3 and and data Akt of of XIAP by phosphorylation of we the phosphorylation of XIAP its type and XIAP-S87D were introduced into A2780S cells. cisplatin for caspase-3 activity and apoptosis were shown in of all of XIAP inhibits cisplatin-induced apoptosis and caspase-3 activity as compared with the cells transfected with XIAP-S87D showed anti-apoptotic function compared with wild type XIAP. the of Akt of XIAP in Akt survival and cells were transfected or with siRNA or adenovirus of antisense of XIAP and with cisplatin or for showed that of XIAP was inhibited by siRNA and antisense of XIAP A and The suppression of XIAP apoptosis in both and cells as compared with the cells with siRNA or adenovirus of which is with recent in cancer cells Y. Cherton-Horvat G. Baird S. Korneluk R.G. Res. 2003; Google Scholar, T. N. K. Y. J. 2003; PubMed Scopus Google Scholar). Furthermore, siRNA and adenovirus of antisense of XIAP of the cells from cisplatin-induced apoptosis B and These data that XIAP is an important survival and mediates cell survival and cisplatin in A2780S cells. XIAP is at transcriptional and of pathway RNA level of XIAP (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google Scholar, K. 2001; PubMed Scopus Google Scholar). ubiquitin ligase XIAP be and in response to DNA including with (16Deveraux Q.L. Reed J.C. Genes Dev. 1999; 13: 239-252Crossref PubMed Scopus (2279) Google Scholar, J.Q. X. M. Li M. H.C. Sun M. 2002; PubMed Scopus Google Scholar, H. N. H. S. T. H. K. S. S. H. Oncogene. 1998; PubMed Scopus Google Scholar). Recent studies showed that XIAP is by the serine protease a proapoptotic protein from the into the cytosol during apoptosis R. J. C. Genes Dev. 2003; 17: PubMed Scopus Google Scholar, S.M. S. Datta P. Z. R. N. T. Alnemri E.S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In we demonstrate that the phosphorylation of XIAP by Akt regulates its ubiquitination and Akt, including and AKT2, interacts with and phosphorylates to of XIAP autoubiquitination and cisplatin-induced ubiquitination. demonstrate that Akt phosphorylates serine of XIAP and that the of of XIAP on phosphorylation at In addition, we have shown that Akt of XIAP is not at transcriptional level and we the of Akt of XIAP at level as Akt has been shown to pathway (7Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar). data that the phosphorylation by Akt be of key mechanisms XIAP levels and function in cells. Accumulated evidence shows that Akt pathway an anti-apoptotic by of at both and post-mitochondrial The proapoptotic protein has been shown to be a major target of Akt at the level (13Zhou H. Li X.M. Meinkoth J. Pittman R.N. J. Cell Biol. 2000; 151: 483-494Crossref PubMed Scopus (389) Google Scholar). the of Akt at the post-mitochondrial level have not been well although a Akt phosphorylation and of caspase-9 (14Cardone 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 (2728) Google Scholar). in that Akt interacts with and phosphorylates XIAP in of caspase-3 activity and apoptosis in response to cisplatin treatment. in which Akt phosphorylation consensus in human (14Cardone 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 (2728) Google Scholar, E. A. H. H. U. T. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google Scholar), the phosphorylation of XIAP is well and we that XIAP could be a major target of Akt function at post-mitochondrial level. have previously that activation of Akt to cisplatin in human ovarian cancer Y. S. Science. 2000; PubMed Scopus Google Scholar). XIAP has been shown to be a of cisplatin in human ovarian cancer J.Q. X. M. Li M. H.C. Sun M. 2002; PubMed Scopus Google Scholar, H. Y. Res. 2000; Google Scholar). In we have that cisplatin decreases XIAP protein in A2780S cells a in XIAP level and and that XIAP transcription is not involved in XIAP by cisplatin. Furthermore, of RING finger domain mutant in which ubiquitin ligase activity was cells more to cisplatin as compared with of wild type XIAP H. 2002; Full Text PDF PubMed Scopus Google Scholar). These that XIAP degradation is an important mechanism to the XIAP and the to cisplatin in human ovarian cancer cells. demonstrate in that of Akt protects XIAP from ubiquitination and degradation induced by cisplatin. Furthermore, XIAP-S87D is more to induced by cisplatin wild type XIAP. Conversely, the shows increased ubiquitination to wild type XIAP In addition, suppression of XIAP by siRNA or antisense of XIAP cisplatin and cell survival These data that Akt of XIAP could be a major mechanism for cisplatin in human ovarian cancer cells. In the data demonstrate for the first that XIAP is by Akt phosphorylates XIAP at residue serine in vitro and in and interacts with XIAP at physiological protein The phosphorylation of XIAP at serine by Akt in of its autoubiquitination and ubiquitination and to cisplatin-induced XIAP caspase-3 and apoptosis. These that in to Bad, is a major physiological substrate of Akt in the of at the post-mitochondrial level. are to the DNA at the H. for XIAP mutant

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The record

Venue

Journal of Biological Chemistry

Topic

Cell death mechanisms and regulation

Field

Biochemistry, Genetics and Molecular Biology

Canadian institutions

Ottawa HospitalUniversity of Ottawa

Funders

National Cancer Institute

Keywords

XIAPInhibitor of apoptosisPhosphorylationProtein kinase BApoptosisCell biologyCancer researchChemistryInhibitor of apoptosis domainBiochemistryBiologyCaspaseProgrammed cell death

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