The tumor suppressor p53 is commonly inhibited under conditions in which the phosphatidylinositide 3′-OH kinase/protein kinase B (PKB)Akt pathway is activated. Intracellular levels of p53 are controlled by the E3 ubiquitin ligase Mdm2. Here we show that PKB inhibits Mdm2 self-ubiquitination via phosphorylation of Mdm2 on Ser166 and Ser188. Stimulation of human embryonic kidney 293 cells with insulin-like growth factor-1 increased Mdm2 phosphorylation on Ser166 and Ser188 in a phosphatidylinositide 3′-OH kinase-dependent manner, and the treatment of both human embryonic kidney 293 and COS-1 cells with phosphatidylinositide 3′-OH kinase inhibitor LY-294002 led to proteasome-mediated Mdm2 degradation. Introduction of a constitutively active form of PKB together with Mdm2 into cells induced phosphorylation of Mdm2 at Ser166 and Ser188 and stabilized Mdm2 protein. Moreover, mouse embryonic fibroblasts lacking PKBα displayed reduced Mdm2 protein levels with a concomitant increase of p53 and p21Cip1, resulting in strongly elevated apoptosis after UV irradiation. In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells. These findings suggest that PKB plays a critical role in controlling of the Mdm2·p53 signaling pathway by regulating Mdm2 stability. The tumor suppressor p53 is commonly inhibited under conditions in which the phosphatidylinositide 3′-OH kinase/protein kinase B (PKB)Akt pathway is activated. Intracellular levels of p53 are controlled by the E3 ubiquitin ligase Mdm2. Here we show that PKB inhibits Mdm2 self-ubiquitination via phosphorylation of Mdm2 on Ser166 and Ser188. Stimulation of human embryonic kidney 293 cells with insulin-like growth factor-1 increased Mdm2 phosphorylation on Ser166 and Ser188 in a phosphatidylinositide 3′-OH kinase-dependent manner, and the treatment of both human embryonic kidney 293 and COS-1 cells with phosphatidylinositide 3′-OH kinase inhibitor LY-294002 led to proteasome-mediated Mdm2 degradation. Introduction of a constitutively active form of PKB together with Mdm2 into cells induced phosphorylation of Mdm2 at Ser166 and Ser188 and stabilized Mdm2 protein. Moreover, mouse embryonic fibroblasts lacking PKBα displayed reduced Mdm2 protein levels with a concomitant increase of p53 and p21Cip1, resulting in strongly elevated apoptosis after UV irradiation. In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells. These findings suggest that PKB plays a critical role in controlling of the Mdm2·p53 signaling pathway by regulating Mdm2 stability. The phosphatidylinositide 3′-OH kinase (PI3K) 1The abbreviations used are: PI3K, phosphatidylinositide 3′-OH kinase; PKB, protein kinase B; m/p-PKB, myristoylated/palmitoylated PKB; Mdm2, murine double minute 2; HEK cells, human embryonic kidney cells; IGF-1, insulin-like growth factor-1; GST, glutathione S-transferase; MEF, mouse embryonic fibroblast; TRITC, tetramethylrhodamine isothiocyanate; E1, ubiquitin-activating enzyme; E3, ubiquitin ligase; BrdUrd, bromodeoxyuridine; HA, hemagglutinin; PBS, phosphate-buffered saline; WT, wild type; KD, kinase dead; GFP, green fluorescent protein.-PKB/Akt pathway is a key component of growth factor-induced cell survival. This pathway has been implicated in suppressing apoptosis in a number of cell types in response to a variety of stimuli, including growth factor withdrawal, cell cycle discordance, loss of cell adhesion, DNA damage, and treatment with anti-Fas antibody or transforming growth factor β (1Datta S.R. Brunet A. Greenberg M.E. 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Chem. 1997; 272: 31515-31524Abstract Full Text Full Text PDF PubMed Scopus (904) Google antibody antibody of and have been (5Andjelkovic M. Alessi D.R. Meier R. Fernandez A. Lamb N.J. Frech M. Cron P. Cohen P. Lucocq J.M. Hemmings B.A. J. Biol. Chem. 1997; 272: 31515-31524Abstract Full Text Full Text PDF PubMed Scopus (904) Google Scholar). was by the of human Mdm2 of C. G. of into The was into the of to The Mdm2 the and by DNA proteins in and on to the was a and was into to B. into the cells, the DNA was and into cells. The resulting used to cells, and the protein was on to the of and by The and a by a These are to and The antibody Mdm2 was by with of human and a by This antibody is to and of PKBα mouse has been in O. M. J. D. Hemmings B.A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). by the wild or O. M. J. D. Hemmings B.A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. F. G. 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The of was by of with antibody to the activation of These that is a protein that is a target degradation R. H. J. 1999; PubMed Scopus Google Scholar, Vousden K.H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google that PKB phosphorylation is Mdm2 Mdm2 stability. the that PKB is to Mdm2, was with or in COS-1 cells. The cells with a protein inhibitor the of of in or cells in cells This was a of in by the levels of These suggest that of a of in the cells may to of Mdm2 protein degradation by PKB than activation of phosphorylation of Mdm2 by PKB was to increase its to phosphorylation of Mdm2 and into COS-1 cells. in was in the of in the of of Ser166 to and Ser188 to in increased Mdm2 stability in the of A double in which both Ser166 and Ser188 to was and was each These that phosphorylation of Mdm2 at Ser166 and Ser188 by PKB Mdm2 protein via of proteasome-mediated degradation. Mdm2 is by PKB in a was with and its in cells. in of Mdm2 in and cells was reduced in and cells. These that Mdm2 phosphorylation Mdm2 of the of suggest that phosphorylation in Mdm2. This to the PI3K/PKB pathway the stability of Mdm2. The protein levels of Mdm2 in and COS-1 cells in the of The of Mdm2 protein in cells, and was by cells with the inhibitor These suggest that the pathway plays a critical role in regulating the stability of Mdm2 protein and that is of in cells. PKBα Mdm2 Protein and to the role of PKB in Mdm2 in we the of Mdm2 protein in and wild by and in Mdm2 was in the in both and cells. The of Mdm2 in was reduced in cells with that of cells. that the levels of Mdm2 protein in cells was than that in cells of Mdm2 at Ser166 was in cells was reduced in cells of Mdm2 at Ser188 was because is that the antibody is to phosphorylation of Ser188 to the in the of human and mouse in PKBα is the PKB in K. K. T. R. K. T. N. Genes Dev. 2001; 15: PubMed Scopus Google and B. A. and the of PKBα in a in Mdm2 protein levels suggest that PKB was to Mdm2 in Mdm2 is a key determinant of p53 we the p53 protein in these cells. in levels of p53 elevated in with the increase in the of was increased with cells p53 and its target an important role in controlling the and cell cycle that growth and apoptosis A. Sci. A. PubMed Scopus Google Scholar, J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, F. A. C. T. J.M. B. 1998; PubMed Scopus Google Scholar), we the cell cycle of in response to UV irradiation. in the displayed a increase in the cell with their These with recent findings by J. N. A. A. N. Mol. Cell. 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