HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 34, 35510-35517, August 20, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/34/35510    most recent M404936200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feng, J. Articles by Hemmings, B. A. Search for Related Content PubMed PubMed Citation Articles by Feng, J. Articles by Hemmings, B. A. Social Bookmarking                      What's this?

Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation^*

Jianhua Feng, Rastislav Tamaskovic, Zhongzhou Yang, Derek P. Brazil¶, Adrian Merlo||, Daniel Hess, and Brian A. Hemmings**

From the Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland and ^||Laboratory of Molecular Neuro-Oncology, Department of Clinical and Biological Sciences, University of Basel, Spitalstrasse 21, Basel CH-4031, Switzerland

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 PKB displayed reduced Mdm2 protein levels with a concomitant increase of p53 and p21^Cip1, 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.

Received for publication, May 4, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Swiss Cancer League Grants KFS0134202-2003 and OCS1167-09-2001.

^¶ Present address: Conway Institute of Biomolecular and Biomedical Research, Dept. of Medicine and Therapeutics, University College Dublin and Dublin Molecular Medicine Centre, Dublin 4, Ireland.

^** To whom correspondence should be addressed. Tel.: 41-61-697-4046; Fax: 41-61-697-3976; E-mail: brian.hemmings{at}fmi.ch.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H.-R. Lee, Z. Toth, Y. C. Shin, J.-S. Lee, H. Chang, W. Gu, T.-K. Oh, M. H. Kim, and J. U. Jung Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 Targets MDM2 To Deregulate the p53 Tumor Suppressor Pathway J. Virol., July 1, 2009; 83(13): 6739 - 6747. [Abstract] [Full Text] [PDF]

				X.L. Jin, V. Chandrakanthan, H.D. Morgan, and C. O'Neill Preimplantation Embryo Development in the Mouse Requires the Latency of TRP53 Expression, Which Is Induced by a Ligand-Activated PI3 Kinase/AKT/MDM2-Mediated Signaling Pathway (Reprinted with Correction) Biol Reprod, July 1, 2009; 81(1): 233 - 242. [Abstract] [Full Text] [PDF]

				Q. Zhou, B. Yan, X. Hu, X.-B. Li, J. Zhang, and J. Fang Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin Mol. Cancer Ther., June 1, 2009; 8(6): 1684 - 1691. [Abstract] [Full Text] [PDF]

				W. Fu, Q. Ma, L. Chen, P. Li, M. Zhang, S. Ramamoorthy, Z. Nawaz, T. Shimojima, H. Wang, Y. Yang, et al. MDM2 Acts Downstream of p53 as an E3 Ligase to Promote FOXO Ubiquitination and Degradation J. Biol. Chem., May 22, 2009; 284(21): 13987 - 14000. [Abstract] [Full Text] [PDF]

				S. Nemoto, M. Nakamura, Y. Osawa, S. Kono, Y. Itoh, Y. Okano, T. Murate, A. Hara, H. Ueda, Y. Nozawa, et al. Sphingosine Kinase Isoforms Regulate Oxaliplatin Sensitivity of Human Colon Cancer Cells through Ceramide Accumulation and Akt Activation J. Biol. Chem., April 17, 2009; 284(16): 10422 - 10432. [Abstract] [Full Text] [PDF]

				H. Alam, J. Weck, E. Maizels, Y. Park, E. J. Lee, M. Ashcroft, and M. Hunzicker-Dunn Role of the Phosphatidylinositol-3-Kinase and Extracellular Regulated Kinase Pathways in the Induction of Hypoxia-Inducible Factor (HIF)-1 Activity and the HIF-1 Target Vascular Endothelial Growth Factor in Ovarian Granulosa Cells in Response to Follicle-Stimulating Hormone Endocrinology, February 1, 2009; 150(2): 915 - 928. [Abstract] [Full Text] [PDF]

				X.L. Jin, V. Chandrakanthan, H.D. Morgan, and C. O'Neill Preimplantation Embryo Development in the Mouse Requires the Latency of TRP53 Expression, Which Is Induced by a Ligand-Activated PI3 Kinase/AKT/MDM2-Mediated Signaling Pathway Biol Reprod, February 1, 2009; 80(2): 286 - 294. [Abstract] [Full Text] [PDF]

				C. Boutell, R. Everett, J. Hilliard, P. Schaffer, A. Orr, and D. Davido Herpes Simplex Virus Type 1 ICP0 Phosphorylation Mutants Impair the E3 Ubiquitin Ligase Activity of ICP0 in a Cell Type-Dependent Manner J. Virol., November 1, 2008; 82(21): 10647 - 10656. [Abstract] [Full Text] [PDF]

				B. Surucu, L. Bozulic, D. Hynx, A. Parcellier, and B. A. Hemmings In Vivo Analysis of Protein Kinase B (PKB)/Akt Regulation in DNA-PKcs-null Mice Reveals a Role for PKB/Akt in DNA Damage Response and Tumorigenesis J. Biol. Chem., October 31, 2008; 283(44): 30025 - 30033. [Abstract] [Full Text] [PDF]

				M. Ferrero, A. Avivar, M. C. Garcia-Macias, and J. F. de Mora Phosphoinositide 3-kinase/AKT Signaling Can Promote AIB1 Stability Independently of GSK3 Phosphorylation Cancer Res., July 1, 2008; 68(13): 5450 - 5459. [Abstract] [Full Text] [PDF]

				C. Hogan, C. Hutchison, L. Marcar, D. Milne, M. Saville, J. Goodlad, N. Kernohan, and D. Meek Elevated Levels of Oncogenic Protein Kinase Pim-1 Induce the p53 Pathway in Cultured Cells and Correlate with Increased Mdm2 in Mantle Cell Lymphoma J. Biol. Chem., June 27, 2008; 283(26): 18012 - 18023. [Abstract] [Full Text] [PDF]

				V. D. Nair and C. W. Olanow Differential Modulation of Akt/Glycogen Synthase Kinase-3{beta} Pathway Regulates Apoptotic and Cytoprotective Signaling Responses J. Biol. Chem., May 30, 2008; 283(22): 15469 - 15478. [Abstract] [Full Text] [PDF]

				V. Lopez-Pajares, M. M. Kim, and Z.-M. Yuan Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding J. Biol. Chem., May 16, 2008; 283(20): 13707 - 13713. [Abstract] [Full Text] [PDF]

				C. O'Neill The potential roles for embryotrophic ligands in preimplantation embryo development Hum. Reprod. Update, May 1, 2008; 14(3): 275 - 288. [Abstract] [Full Text] [PDF]

				T. Kimura, M. Tomooka, N. Yamano, K. Murayama, S. Matoba, H. Umehara, Y. Kanai, and T. Nakano AKT signaling promotes derivation of embryonic germ cells from primordial germ cells Development, March 1, 2008; 135(5): 869 - 879. [Abstract] [Full Text] [PDF]

				F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]

				Y. Li, V. Chandrakanthan, M. L Day, and C. O'Neill Direct Evidence for the Action of Phosphatidylinositol (3,4,5)-Trisphosphate-Mediated Signal Transduction in the 2-Cell Mouse Embryo Biol Reprod, November 1, 2007; 77(5): 813 - 821. [Abstract] [Full Text] [PDF]

				D. J. Groskreutz, M. M. Monick, T. O. Yarovinsky, L. S. Powers, D. E. Quelle, S. M. Varga, D. C. Look, and G. W. Hunninghake Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells J. Immunol., September 1, 2007; 179(5): 2741 - 2747. [Abstract] [Full Text] [PDF]

				L.-H. Chen, J. Fang, H. Li, W. Demark-Wahnefried, and X. Lin Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway Mol. Cancer Ther., September 1, 2007; 6(9): 2581 - 2590. [Abstract] [Full Text] [PDF]

				U. V. Pedmale and E. Liscum Regulation of Phototropic Signaling in Arabidopsis via Phosphorylation State Changes in the Phototropin 1-interacting Protein NPH3 J. Biol. Chem., July 6, 2007; 282(27): 19992 - 20001. [Abstract] [Full Text] [PDF]

				S. Ramalingam, P. Honkanen, L. Young, T. Shimura, J. Austin, P. S. Steeg, and S. Nishizuka Quantitative Assessment of the p53-Mdm2 Feedback Loop Using Protein Lysate Microarrays Cancer Res., July 1, 2007; 67(13): 6247 - 6252. [Abstract] [Full Text] [PDF]

				A. Moumen, S. Patane, A. Porras, R. Dono, and F. Maina Met acts on Mdm2 via mTOR to signal cell survival during development Development, April 1, 2007; 134(7): 1443 - 1451. [Abstract] [Full Text] [PDF]

				M. Li, Z. Zhang, D. L. Hill, H. Wang, and R. Zhang Curcumin, a Dietary Component, Has Anticancer, Chemosensitization, and Radiosensitization Effects by Down-regulating the MDM2 Oncogene through the PI3K/mTOR/ETS2 Pathway Cancer Res., March 1, 2007; 67(5): 1988 - 1996. [Abstract] [Full Text] [PDF]

				M. Malmlof, E. Roudier, J. Hogberg, and U. Stenius MEK-ERK-mediated Phosphorylation of Mdm2 at Ser-166 in Hepatocytes: Mdm2 IS ACTIVATED IN RESPONSE TO INHIBITED Akt SIGNALING J. Biol. Chem., January 26, 2007; 282(4): 2288 - 2296. [Abstract] [Full Text] [PDF]

				K. H. Limesand, K. L. Schwertfeger, and S. M. Anderson MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells Mol. Cell. Biol., December 1, 2006; 26(23): 8840 - 8856. [Abstract] [Full Text] [PDF]

				B. Lefebvre, C. Brand, S. Flajollet, and P. Lefebvre Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor {beta}2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway Mol. Endocrinol., September 1, 2006; 20(9): 2109 - 2121. [Abstract] [Full Text] [PDF]

				M. Baserga, M. A. Hale, X. Ke, Z. M. Wang, X. Yu, C. W. Callaway, R. A. McKnight, and R. H. Lane Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit response in the IUGR rat kidney Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R412 - R418. [Abstract] [Full Text] [PDF]

				C. V. Garat, D. Fankell, P. F. Erickson, J. E.-B. Reusch, N. N. Bauer, I. F. McMurtry, and D. J. Klemm Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells. Mol. Cell. Biol., July 1, 2006; 26(13): 4934 - 4948. [Abstract] [Full Text] [PDF]

				A. Toth, P. Nickson, L. L. Qin, and P. Erhardt Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase J. Biol. Chem., February 10, 2006; 281(6): 3679 - 3689. [Abstract] [Full Text] [PDF]

				Z.-Z. Yang, O. Tschopp, N. Di-Poi, E. Bruder, A. Baudry, B. Dummler, W. Wahli, and B. A. Hemmings Dosage-Dependent Effects of Akt1/Protein Kinase B{alpha} (PKB{alpha}) and Akt3/PKB{gamma} on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice Mol. Cell. Biol., December 1, 2005; 25(23): 10407 - 10418. [Abstract] [Full Text] [PDF]

				S. L. Harris, G. Gil, H. Robins, W. Hu, K. Hirshfield, E. Bond, G. Bond, and A. J. Levine Detection of functional single-nucleotide polymorphisms that affect apoptosis PNAS, November 8, 2005; 102(45): 16297 - 16302. [Abstract] [Full Text] [PDF]

				E. Hertlein, J. Wang, K. J. Ladner, N. Bakkar, and D. C. Guttridge RelA/p65 Regulation of I{kappa}B{beta} Mol. Cell. Biol., June 15, 2005; 25(12): 4956 - 4968. [Abstract] [Full Text] [PDF]

				H. Rangone, R. Pardo, E. Colin, J.-A. Girault, F. Saudou, and S. Humbert Phosphorylation of Arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced Toxicity by Rescuing Proteasome Impairment J. Biol. Chem., June 10, 2005; 280(23): 22021 - 22028. [Abstract] [Full Text] [PDF]

				M. Phelps, A. Phillips, M. Darley, and J. P. Blaydes MEK-ERK Signaling Controls Hdm2 Oncoprotein Expression by Regulating hdm2 mRNA Export to the Cytoplasm J. Biol. Chem., April 29, 2005; 280(17): 16651 - 16658. [Abstract] [Full Text] [PDF]

				J. Fang, C. Xia, Z. Cao, J. Z. Zheng, E. Reed, and B.-H. Jiang Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways FASEB J, March 1, 2005; 19(3): 342 - 353. [Abstract] [Full Text] [PDF]

				S.L. HARRIS, G. GIL, W. HU, H. ROBINS, E. BOND, K. HIRSHFIELD, Z. FENG, X. YU, A.K. TERESKY, G. BOND, et al. Single-Nucleotide Polymorphisms in the p53 Pathway Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 111 - 119. [Abstract] [PDF]

				J. Feng, J. Park, P. Cron, D. Hess, and B. A. Hemmings Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase J. Biol. Chem., September 24, 2004; 279(39): 41189 - 41196. [Abstract] [Full Text] [PDF]