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Kinase Is Frequently Elevated in Human Cancers and Its Constitutive Activation Is Required for Oncogenic Transformation in NIH3T3 Cells
From the Department of Pathology and Laboratory Medicine and the
Molecular Oncology Program,*
University of South Florida
College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida;
the Cancer Research Department,
Berlex
Biosciences, Richmond, California; and the Kimmel Cancer
Center,
Thomas Jefferson University,
Philadelphia, Pennsylvania
Extensive studies have demonstrated that the Akt/AKT1 pathway is essential for cell survival and inhibition of apoptosis; however, alterations of Akt/AKT1 in human primary tumors have not been well documented. In this report, significantly increased AKT1 kinase activity was detected in primary carcinomas of prostate (16 of 30), breast (19 of 50), and ovary (11 of 28). The results were confirmed by Western blot and immunohistochemical staining analyses with phospho-Ser473 Akt antibody. The majority of AKT1-activated tumors are high grade and stage III/lV (13 of 16 prostate, 15 of 19 breast, and 8 of 11 ovarian carcinomas). Previous studies showed that wild-type AKT1 was unable to transform NIH3T3 cells. To demonstrate the biological significance of AKT1 activation in human cancer, constitutively activated AKT1 (Myr-Akt) was introduced into NIH3T3 cells. Overexpression of Myr-Akt in the stably transfected cells resulted in malignant phenotype, as determined by growth in soft agar and tumor formation in nude mice. These data indicate that AKT1 kinase, which is frequently activated in human cancer, is a determinant in oncogenesis and a potential target for cancer intervention.
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Z.-q. Yuan, R. I. Feldman, G. E. Sussman, D. Coppola, S. V. Nicosia, and J. Q. Cheng AKT2 Inhibition of Cisplatin-induced JNK/p38 and Bax Activation by Phosphorylation of ASK1: IMPLICATION OF AKT2 IN CHEMORESISTANCE J. Biol. Chem., June 20, 2003; 278(26): 23432 - 23440. [Abstract] [Full Text] [PDF]
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T. M. Gritsko, D. Coppola, J. E. Paciga, L. Yang, M. Sun, S. A. Shelley, J. V. Fiorica, S. V. Nicosia, and J. Q. Cheng Activation and Overexpression of Centrosome Kinase BTAK/Aurora-A in Human Ovarian Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1420 - 1426. [Abstract] [Full Text] [PDF]
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H. Kurokawa and C. L. Arteaga ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms Clin. Cancer Res., January 1, 2003; 9(1): 511S - 515S. [Abstract] [Full Text] [PDF]
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P. Dhawan, A. B. Singh, D. L. Ellis, and A. Richmond Constitutive Activation of Akt/Protein Kinase B in Melanoma Leads to Up-Regulation of Nuclear Factor-{kappa}B and Tumor Progression Cancer Res., December 15, 2002; 62(24): 7335 - 7342. [Abstract] [Full Text] [PDF]
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A. D. Basso, D. B. Solit, G. Chiosis, B. Giri, P. Tsichlis, and N. Rosen Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function J. Biol. Chem., October 11, 2002; 277(42): 39858 - 39866. [Abstract] [Full Text] [PDF]
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H. C. Dan, M. Sun, L. Yang, R. I. Feldman, X.-M. Sui, C. C. Ou, M. Nellist, R. S. Yeung, D. J. J. Halley, S. V. Nicosia, et al. Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Tuberous Sclerosis Tumor Suppressor Complex by Phosphorylation of Tuberin J. Biol. Chem., September 13, 2002; 277(38): 35364 - 35370. [Abstract] [Full Text] [PDF]
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K. Moelling, K. Schad, M. Bosse, S. Zimmermann, and M. Schweneker Regulation of Raf-Akt Cross-talk J. Biol. Chem., August 16, 2002; 277(34): 31099 - 31106. [Abstract] [Full Text] [PDF]
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F. M. Yakes, W. Chinratanalab, C. A. Ritter, W. King, S. Seelig, and C. L. Arteaga Herceptin-induced Inhibition of Phosphatidylinositol-3 Kinase and Akt Is Required for Antibody-mediated Effects on p27, Cyclin D1, and Antitumor Action Cancer Res., July 15, 2002; 62(14): 4132 - 4141. [Abstract] [Full Text] [PDF]
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B. Tanno, A. Negroni, R. Vitali, M. C. Pirozzoli, V. Cesi, C. Mancini, B. Calabretta, and G. Raschella Expression of Insulin-like Growth Factor-binding Protein 5 in Neuroblastoma Cells Is Regulated at the Transcriptional Level by c-Myb and B-Myb via Direct and Indirect Mechanisms J. Biol. Chem., June 21, 2002; 277(26): 23172 - 23180. [Abstract] [Full Text] [PDF]
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X. Zeng, H. Xu, and R. I. Glazer Transformation of Mammary Epithelial Cells by 3-Phosphoinositide-dependent Protein Kinase-1 (PDK1) Is Associated with the Induction of Protein Kinase C{alpha} Cancer Res., June 1, 2002; 62(12): 3538 - 3543. [Abstract] [Full Text] [PDF]
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K. J. Hurt, B. Musicki, M. A. Palese, J. K. Crone, R. E. Becker, J. L. Moriarity, S. H. Snyder, and A. L. Burnett Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection PNAS, March 19, 2002; 99(6): 4061 - 4066. [Abstract] [Full Text] [PDF]
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