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Science 11 October 1991:
Vol. 254. no. 5029, pp. 274 - 277
DOI: 10.1126/science.1833819
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Articles

Science, Vol 254, Issue 5029, 274-277
Copyright © 1991 by American Association for the Advancement of Science

articles

A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region

A Bellacosa, Testa JR, SP Staal, and PN Tsichlis

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.

The v-akt oncogene codes for a 105-kilodalton fusion phosphoprotein containing Gag sequences at its amino terminus. Sequence analysis of v-akt and biochemical characterization of its product revealed that it codes for a protein kinase C-related serine-threonine kinase whose cellular homolog is expressed in most tissues, with the highest amount found in thymus. Although Akt is a serine-threonine kinase, part of its regulatory region is similar to the Src homology-2 domain, a structural motif characteristic of cytoplasmic tyrosine kinases that functions in protein-protein interactions. This suggests that Akt may form a functional link between tyrosine and serine-threonine phosphorylation pathways.


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Spatiotemporal Analysis of Differential Akt Regulation in Plasma Membrane Microdomains.
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Regulation of Phosphorylation of Thr-308 of Akt, Cell Proliferation, and Survival by the B55{alpha} Regulatory Subunit Targeting of the Protein Phosphatase 2A Holoenzyme to Akt.
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Cholesterol Sensitivity of Endogenous and Myristoylated Akt.
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PTEN, more than the AKT pathway.
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Nodal signalling and apoptosis.
H. Wang and B. K Tsang (2007)
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Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition.
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Akt Attenuation of the Serine Protease Activity of HtrA2/Omi through Phosphorylation of Serine 212.
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Arch Dermatol 143, 504-506
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Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs.
Y. Tambe, A. Yoshioka-Yamashita, K.-i. Mukaisho, S. Haraguchi, T. Chano, T. Isono, T. Kawai, Y. Suzuki, R. Kushima, T. Hattori, et al. (2007)
Carcinogenesis 28, 777-784
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Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines.
W.-T. Choi, M. Kaul, S. Kumar, J. Wang, I. M. K. Kumar, C.-Z. Dong, J. An, S. A. Lipton, and Z. Huang (2007)
J. Biol. Chem. 282, 7154-7163
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Z. Salah, M. Maoz, E. Pokroy, M. Lotem, R. Bar-Shavit, and B. Uziely (2007)
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I. G. Maroulakou, W. Oemler, S. P. Naber, and P. N. Tsichlis (2007)
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Quantitative Analysis of Anti-apoptotic Function of Akt in Akt1 and Akt2 Double Knock-out Mouse Embryonic Fibroblast Cells under Normal and Stressed Conditions.
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Interdomain Conformational Changes in Akt Activation Revealed by Chemical Cross-linking and Tandem Mass Spectrometry.
B. X. Huang and H.-Y. Kim (2006)
Mol. Cell. Proteomics 5, 1045-1053
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Kinetic Mechanism of AKT/PKB Enzyme Family.
X. Zhang, S. Zhang, H. Yamane, R. Wahl, A. Ali, J. A. Lofgren, and R. L. Kendall (2006)
J. Biol. Chem. 281, 13949-13956
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Cyclic and characteristic expression of phosphorylated Akt in human endometrium and decidual cells in vivo and in vitro.
A. Toyofuku, T. Hara, T. Taguchi, Y. Katsura, K. Ohama, and Y. Kudo (2006)
Hum. Reprod. 21, 1122-1128
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Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets.
S. Kim, J. Jin, and S. P. Kunapuli (2006)
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Akt Phosphorylates and Regulates Pdcd4 Tumor Suppressor Protein.
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Q. Liu, L. R. White, S. A. Clark, D. J. Heffner, B. W. Winston, L. A. Tibbles, and D. A. Muruve (2005)
J. Virol. 79, 14507-14515
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Breast Cancer-Associated PIK3CA Mutations Are Oncogenic in Mammary Epithelial Cells.
S. J. Isakoff, J. A. Engelman, H. Y. Irie, J. Luo, S. M. Brachmann, R. V. Pearline, L. C. Cantley, and J. S. Brugge (2005)
Cancer Res. 65, 10992-11000
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Bone Morphogenetic Protein-2-Induced Transformation Involves the Activation of Mammalian Target of Rapamycin.
E. M. Langenfeld, Y. Kong, and J. Langenfeld (2005)
Mol. Cancer Res. 3, 679-684
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Molecular Cloning and Characterization of the Human AKT1 Promoter Uncovers Its Up-regulation by the Src/Stat3 Pathway.
S. Park, D. Kim, S. Kaneko, K. M. Szewczyk, S. V. Nicosia, H. Yu, R. Jove, and J. Q. Cheng (2005)
J. Biol. Chem. 280, 38932-38941
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Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate.
D. J. VanderWeele and C. M. Rudin (2005)
Mol. Cancer Res. 3, 635-644
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AKT Activation Promotes Metastasis in a Mouse Model of Follicular Thyroid Carcinoma.
C. S. Kim, V. V. Vasko, Y. Kato, M. Kruhlak, M. Saji, S.-Y. Cheng, and M. D. Ringel (2005)
Endocrinology 146, 4456-4463
   Abstract »    Full Text »    PDF »
Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells.
S. Dihlmann, M. Kloor, C. Fallsehr, and M. von Knebel Doeberitz (2005)
Carcinogenesis 26, 1503-1512
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FasL (CD95L/APO-1L) Resistance of Neurons Mediated by Phosphatidylinositol 3-Kinase-Akt/Protein Kinase B-Dependent Expression of Lifeguard/Neuronal Membrane Protein 35.
C. P. Beier, J. Wischhusen, M. Gleichmann, E. Gerhardt, A. Pekanovic, A. Krueger, V. Taylor, U. Suter, P. H. Krammer, M. Endres, et al. (2005)
J. Neurosci. 25, 6765-6774
   Abstract »    Full Text »    PDF »
ArgBP2{gamma} Interacts with Akt and p21-activated Kinase-1 and Promotes Cell Survival.
Z.-q. Yuan, D. Kim, S. Kaneko, M. Sussman, G. M. Bokoch, G. D. Kruh, S. V. Nicosia, J. R. Testa, and J. Q. Cheng (2005)
J. Biol. Chem. 280, 21483-21490
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Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo.
Y. Luo, A. R. Shoemaker, X. Liu, K. W. Woods, S. A. Thomas, R. de Jong, E. K. Han, T. Li, V. S. Stoll, J. A. Powlas, et al. (2005)
Mol. Cancer Ther. 4, 977-986
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{gamma}-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion.
M. J. Rane, D. Gozal, W. Butt, E. Gozal, W. M. Pierce Jr, S. Z. Guo, R. Wu, A. D. Goldbart, V. Thongboonkerd, K. R. McLeish, et al. (2005)
J. Immunol. 174, 7242-7249
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Roles of the Ras-MEK-Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase-Akt-mTOR Pathways in Jaagsiekte Sheep Retrovirus-Induced Transformation of Rodent Fibroblast and Epithelial Cell Lines.
N. Maeda, W. Fu, A. Ortin, M. de las Heras, and H. Fan (2005)
J. Virol. 79, 4440-4450
   Abstract »    Full Text »    PDF »
Inhibition of Protein Synthesis by Y Box-Binding Protein 1 Blocks Oncogenic Cell Transformation.
A. G. Bader and P. K. Vogt (2005)
Mol. Cell. Biol. 25, 2095-2106
   Abstract »    Full Text »    PDF »
Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles.
E. Yamada, S. Okada, T. Saito, K. Ohshima, M. Sato, T. Tsuchiya, Y. Uehara, H. Shimizu, and M. Mori (2005)
J. Cell Biol. 168, 921-928
   Abstract »    Full Text »    PDF »
Prognostic Significance of Activated Akt Expression in Melanoma: A Clinicopathologic Study of 292 Cases.
D. L. Dai, M. Martinka, and G. Li (2005)
J. Clin. Oncol. 23, 1473-1482
   Abstract »    Full Text »    PDF »
Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization.
M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto (2005)
Am. J. Pathol. 166, 737-749
   Abstract »    Full Text »    PDF »
Spatio-temporal Dynamics of Protein Kinase B/Akt Signaling Revealed by a Genetically Encoded Fluorescent Reporter.
M. T. Kunkel, Q. Ni, R. Y. Tsien, J. Zhang, and A. C. Newton (2005)
J. Biol. Chem. 280, 5581-5587
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic.
S. Kang, A. G. Bader, and P. K. Vogt (2005)
PNAS 102, 802-807
   Abstract »    Full Text »    PDF »
Mitochondria and Cancer: Warburg Addressed.
D.C. WALLACE (2005)
Cold Spring Harb Symp Quant Biol 70, 363-374
   Abstract »    PDF »
Inhibition of Akt/Protein Kinase B Signaling by Naltrindole in Small Cell Lung Cancer Cells.
Y. L. Chen, P. Y. Law, and H. H. Loh (2004)
Cancer Res. 64, 8723-8730
   Abstract »    Full Text »    PDF »
Putting the Rap on Akt.
J. E. Thompson and C. B. Thompson (2004)
J. Clin. Oncol. 22, 4217-4226
   Abstract »    Full Text »    PDF »
Structural Basis for the Co-activation of Protein Kinase B by T-cell Leukemia-1 (TCL1) Family Proto-oncoproteins.
D. Auguin, P. Barthe, C. Royer, M.-H. Stern, M. Noguchi, S. T. Arold, and C. Roumestand (2004)
J. Biol. Chem. 279, 35890-35902
   Abstract »    Full Text »    PDF »
The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway.
I. Sansal and W. R. Sellers (2004)
J. Clin. Oncol. 22, 2954-2963
   Abstract »    Full Text »    PDF »
PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt.
J.-Y. Ahn, Y. Hu, T. G. Kroll, P. Allard, and K. Ye (2004)
PNAS 101, 6993-6998
   Abstract »    Full Text »    PDF »
The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival.
S. Cooray (2004)
J. Gen. Virol. 85, 1065-1076
   Abstract »    Full Text »    PDF »
Role of Protein Kinase B-Dependent Signaling in Lung Tumorigenesis.
J. M. Kurie (2004)
Chest 125, 141S-144S
   Abstract »    Full Text »    PDF »
Protein Kinase B/Akt Regulates Coxsackievirus B3 Replication through a Mechanism Which Is Not Caspase Dependent.
M. Esfandiarei, H. Luo, B. Yanagawa, A. Suarez, D. Dabiri, J. Zhang, and B. M. McManus (2004)
J. Virol. 78, 4289-4298
   Abstract »    Full Text »    PDF »
Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues.
S. S. Castillo, J. Brognard, P. A. Petukhov, C. Zhang, J. Tsurutani, C. A. Granville, M. Li, M. Jung, K. A. West, J. G. Gills, et al. (2004)
Cancer Res. 64, 2782-2792
   Abstract »    Full Text »    PDF »
Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP{alpha} growth inhibitory activity.
G.-L. Wang, P. Iakova, M. Wilde, S. Awad, and N. A. Timchenko (2004)
Genes & Dev. 18, 912-925
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Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP).
H. C. Dan, M. Sun, S. Kaneko, R. I. Feldman, S. V. Nicosia, H.-G. Wang, B. K. Tsang, and J. Q. Cheng (2004)
J. Biol. Chem. 279, 5405-5412
   Abstract »    Full Text »    PDF »
Akt Activation in Platelets Depends on Gi Signaling Pathways.
S. Kim, J. Jin, and S. P. Kunapuli (2004)
J. Biol. Chem. 279, 4186-4195
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor-dependent, NF-{kappa}B-independent Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Inhibits Ultraviolet Irradiation-induced Caspases-3, -8, and -9 in Human Keratinocytes.
H. Q. Wang, T. Quan, T. He, T. F. Franke, J. J. Voorhees, and G. J. Fisher (2003)
J. Biol. Chem. 278, 45737-45745
   Abstract »    Full Text »    PDF »
Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival.
J. C. Rathmell, C. J. Fox, D. R. Plas, P. S. Hammerman, R. M. Cinalli, and C. B. Thompson (2003)
Mol. Cell. Biol. 23, 7315-7328
   Abstract »    Full Text »    PDF »
Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway.
A. G. Bader, K. A. Felts, N. Jiang, H. W. Chang, and P. K. Vogt (2003)
PNAS 100, 12384-12389
   Abstract »    Full Text »    PDF »
Specificity in the activation and control of transcription factor E2F-dependent apoptosis.
T. C. Hallstrom and J. R. Nevins (2003)
PNAS 100, 10848-10853
   Abstract »    Full Text »    PDF »
Transformation of Mouse Fibroblasts by Jaagsiekte Sheep Retrovirus Envelope Does Not Require Phosphatidylinositol 3-Kinase.
N. Maeda, Y. Inoshima, D. A. Fruman, S. M. Brachmann, and H. Fan (2003)
J. Virol. 77, 9951-9959
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Osteopontin Stimulates Cell Motility and Nuclear Factor {kappa}B-mediated Secretion of Urokinase Type Plasminogen Activator through Phosphatidylinositol 3-Kinase/Akt Signaling Pathways in Breast Cancer Cells.
R. Das, G. H. Mahabeleshwar, and G. C. Kundu (2003)
J. Biol. Chem. 278, 28593-28606
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Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3'-Kinase Pathway.
W. Kim, S.-O. Moon, S. Lee, M. J. Sung, S. H. Kim, and S. K. Park (2003)
Arterioscler. Thromb. Vasc. Biol. 23, 1377-1383
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Use of RNA Interference-mediated Gene Silencing and Adenoviral Overexpression to Elucidate the Roles of AKT/Protein Kinase B Isoforms in Insulin Actions.
T. Katome, T. Obata, R. Matsushima, N. Masuyama, L. C. Cantley, Y. Gotoh, K. Kishi, H. Shiota, and Y. Ebina (2003)
J. Biol. Chem. 278, 28312-28323
   Abstract »    Full Text »    PDF »
Increased Phospho-AKT (Ser473) Expression in Bronchial Dysplasia: Implications for Lung Cancer Prevention Studies.
A. S. Tsao, T. McDonnell, S. Lam, J. B. Putnam, N. Bekele, W. K. Hong, and J. M. Kurie (2003)
Cancer Epidemiol. Biomarkers Prev. 12, 660-664
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Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: The MPAKT model.
P. K. Majumder, J. J. Yeh, D. J. George, P. G. Febbo, J. Kum, Q. Xue, R. Bikoff, H. Ma, P. W. Kantoff, T. R. Golub, et al. (2003)
PNAS 100, 7841-7846
   Abstract »    Full Text »    PDF »
Evidence That Phosphatidylinositol 3-Kinase- and Mitogen-activated Protein Kinase Kinase-4/c-Jun NH2-terminal Kinase-dependent Pathways Cooperate to Maintain Lung Cancer Cell Survival.
H.-Y. Lee, H. Srinivas, D. Xia, Y. Lu, R. Superty, R. LaPushin, C. Gomez-Manzano, A. M. Gal, G. L. Walsh, T. Force, et al. (2003)
J. Biol. Chem. 278, 23630-23638
   Abstract »    Full Text »    PDF »
Akt as a possible intracellular mediator for decidualization in human endometrial stromal cells.
O. Yoshino, Y. Osuga, Y. Hirota, K. Koga, T. Yano, O. Tsutsumi, and Y. Taketani (2003)
Mol. Hum. Reprod. 9, 265-269
   Abstract »    Full Text »    PDF »
Targeting the Phosphatidylinositol 3-Kinase/Akt Pathway for Enhancing Breast Cancer Cells to Radiotherapy.
K. Liang, W. Jin, C. Knuefermann, M. Schmidt, G. B. Mills, K. K. Ang, L. Milas, and Z. Fan (2003)
Mol. Cancer Ther. 2, 353-360
   Abstract »    Full Text »    PDF »
Akt Activation Promotes Degradation of Tuberin and FOXO3a via the Proteasome.
D. R. Plas and C. B. Thompson (2003)
J. Biol. Chem. 278, 12361-12366
   Abstract »    Full Text »    PDF »
Akt as a Mediator of Secretory Phospholipase A2 Receptor-Involved Inducible Nitric Oxide Synthase Expression.
D.-W. Park, J.-R. Kim, S.-Y. Kim, J.-K. Sonn, O.-S. Bang, S.-S. Kang, J.-H. Kim, and S.-H. Baek (2003)
J. Immunol. 170, 2093-2099
   Abstract »    Full Text »    PDF »
Dopamine Induces a PI3-Kinase-Independent Activation of Akt in Striatal Neurons: A New Route to cAMP Response Element-Binding Protein Phosphorylation.
K. Brami-Cherrier, E. Valjent, M. Garcia, C. Pages, R. A. Hipskind, and J. Caboche (2002)
J. Neurosci. 22, 8911-8921
   Abstract »    Full Text »    PDF »
Simian Virus 40 Small Tumor Antigen Activates AKT and Telomerase and Induces Anchorage-Independent Growth of Human Epithelial Cells.
H. Yuan, T. Veldman, K. Rundell, and R. Schlegel (2002)
J. Virol. 76, 10685-10691
   Abstract »    Full Text »    PDF »
Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression.
J. C. M. Morel, C. C. Park, K. Zhu, P. Kumar, J. H. Ruth, and A. E. Koch (2002)
J. Biol. Chem. 277, 34679-34691
   Abstract »    Full Text »    PDF »
The Role of Asp-462 in Regulating Akt Activity.
J. Xu, D. Liu, and Z. Songyang (2002)
J. Biol. Chem. 277, 35561-35566
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3beta Is Activated by cAMP and Plays an Active Role in the Regulation of Melanogenesis.
M. Khaled, L. Larribere, K. Bille, E. Aberdam, J.-P. Ortonne, R. Ballotti, and C. Bertolotto (2002)
J. Biol. Chem. 277, 33690-33697
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Multiple Phosphoinositide 3-Kinase-Dependent Steps in Activation of Protein Kinase B.
M. P. Scheid, P. A. Marignani, and J. R. Woodgett (2002)
Mol. Cell. Biol. 22, 6247-6260
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The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP3 levels.
S. Oldham, H. Stocker, M. Laffargue, F. Wittwer, M. Wymann, and E. Hafen (2002)
Development 129, 4103-4109
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Insulin-like Growth Factor-1-mediated AKT Activation Postpones the Onset of Ultraviolet B-induced Apoptosis, Providing More Time for Cyclobutane Thymine Dimer Removal in Primary Human Keratinocytes.
D. Decraene, P. Agostinis, R. Bouillon, H. Degreef, and M. Garmyn (2002)
J. Biol. Chem. 277, 32587-32595
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cAMP Inhibition of Akt Is Mediated by Activated and Phosphorylated Rap1b.
L. Lou, J. Urbani, F. Ribeiro-Neto, and D. L. Altschuler (2002)
J. Biol. Chem. 277, 32799-32806
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Akt-Dependent Phosphorylation Specifically Regulates Cot Induction of NF-{kappa}B-Dependent Transcription.
L. P. Kane, M. N. Mollenauer, Z. Xu, C. W. Turck, and A. Weiss (2002)
Mol. Cell. Biol. 22, 5962-5974
   Abstract »    Full Text »    PDF »
Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor alpha -induced AKT2 through Activation of the NFkappa B Pathway in Human Epithelial Cells.
Z.-q. Yuan, R. I. Feldman, M. Sun, N. E. Olashaw, D. Coppola, G. E. Sussman, S. A. Shelley, S. V. Nicosia, and J. Q. Cheng (2002)
J. Biol. Chem. 277, 29973-29982
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Cross-Linking CD98 Promotes Integrin-like Signaling and Anchorage-independent Growth.
R. C. Rintoul, R. C. Buttery, A. C Mackinnon, W. S. Wong, D. Mosher, C. Haslett, and T. Sethi (2002)
Mol. Biol. Cell 13, 2841-2852
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Constitutive and Inducible Akt Activity Promotes Resistance to Chemotherapy, Trastuzumab, or Tamoxifen in Breast Cancer Cells.
A. S. Clark, K. West, S. Streicher, and P. A. Dennis (2002)
Mol. Cancer Ther. 1, 707-717
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Inactivation of the Antiapoptotic Phosphatidylinositol 3-Kinase-Akt Pathway by the Combined Treatment of Taxol and Mitogen-activated Protein Kinase Kinase Inhibition.
J. P. MacKeigan, D. J. Taxman, D. Hunter, H. S. Earp III, L. M. Graves, and J. P-Y. Ting (2002)
Clin. Cancer Res. 8, 2091-2099
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Inhibition of Nuclear Factor {kappa}B Activation in PC3 Cells by Genistein Is Mediated via Akt Signaling Pathway.
Y. Li and F. H. Sarkar (2002)
Clin. Cancer Res. 8, 2369-2377
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