This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Motti, M. L. Articles by Viglietto, G. Search for Related Content PubMed PubMed Citation Articles by Motti, M. L. Articles by Viglietto, G.

(American Journal of Pathology. 2005;166:737-749.)
© 2005 American Society for Investigative Pathology

Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27^kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway

Regulation of p27^kip1 Expression and Localization

Maria Letizia Motti^*, Daniela Califano, Giancarlo Troncone, Carmela De Marco^*, Ilenia Migliaccio, Emiliano Palmieri^*, Luciano Pezzullo, Lucio Palombini, Alfredo Fusco^* and Giuseppe Viglietto^¶

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano,^* the Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, and the Dipartimento di Scienze Biomorfologiche, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, Napoli; the Istituto Nazionale Tumori, Napoli; and the Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore,"^¶ Università Magna Graecia, Catanzaro, Italy

Functional inactivation of the tumor suppressor p27^kip1 in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27^kip1 is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27. Results obtained with phospho-specific antibodies and with transfection of nonphosphorylable p27^kip1 mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27^kip1 mislocalization in thyroid cancer cells occurred via phosphorylation of p27^kip1 at T157 and T198 (but not at S10 or T187). Finally, we evaluated whether these results were applicable to human tumors. Analysis of 100 thyroid carcinomas indicated that p27^kip1 phosphorylation at T157/T198 and cytoplasmic mislocalization were preferentially associated with activation of the PI3K/AKT pathway. Thus the PI3/AKT pathway and its effector p27^kip1 play major roles in thyroid carcinogenesis.

This article has been cited by other articles:

				S. Shetty, P. Shetty, S. Idell, T. Velusamy, Y. P. Bhandary, and R. S. Shetty Regulation of Plasminogen Activator Inhibitor-1 Expression by Tumor Suppressor Protein p53 J. Biol. Chem., July 11, 2008; 283(28): 19570 - 19580. [Abstract] [Full Text] [PDF]

				A. J. Robinson-White, H.-P. Hsiao, W. W. Leitner, E. Greene, A. Bauer, N. L. Krett, M. Nesterova, and C. A. Stratakis Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1020 - 1029. [Abstract] [Full Text] [PDF]

				L. M. Porchia, M. Guerra, Y.-C. Wang, Y. Zhang, A. V. Espinosa, M. Shinohara, S. K. Kulp, L. S. Kirschner, M. Saji, C.-S. Chen, et al. 2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} Acetamide (OSU-03012), a Celecoxib Derivative, Directly Targets p21-Activated Kinase Mol. Pharmacol., November 1, 2007; 72(5): 1124 - 1131. [Abstract] [Full Text] [PDF]

				Q. Wang, Y. Zhou, X. Wang, D. H. Chung, and B. M. Evers Regulation of PTEN Expression in Intestinal Epithelial Cells by c-Jun NH2-Terminal Kinase Activation and Nuclear Factor-{kappa}B Inhibition Cancer Res., August 15, 2007; 67(16): 7773 - 7781. [Abstract] [Full Text] [PDF]

				G. Chiappetta, C. De Marco, A. Quintiero, D. Califano, S. Gherardi, D. Malanga, M. Scrima, C. Montero-Conde, L. Cito, M. Monaco, et al. Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer Endocr. Relat. Cancer, June 1, 2007; 14(2): 405 - 420. [Abstract] [Full Text] [PDF]

				A. Cretu, J. M. Roth, M. Caunt, A. Akalu, D. Policarpio, S. Formenti, P. Gagne, L. Liebes, and P. C. Brooks Disruption of Endothelial Cell Interactions with the Novel HU177 Cryptic Collagen Epitope Inhibits Angiogenesis Clin. Cancer Res., May 15, 2007; 13(10): 3068 - 3078. [Abstract] [Full Text] [PDF]

				M. Shinohara, Y. J. Chung, M. Saji, and M. D. Ringel AKT in Thyroid Tumorigenesis and Progression Endocrinology, March 1, 2007; 148(3): 942 - 947. [Abstract] [Full Text] [PDF]

				V. Vasko, A. V. Espinosa, W. Scouten, H. He, H. Auer, S. Liyanarachchi, A. Larin, V. Savchenko, G. L. Francis, A. de la Chapelle, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion PNAS, February 20, 2007; 104(8): 2803 - 2808. [Abstract] [Full Text] [PDF]

				N. Yeager, A. Klein-Szanto, S. Kimura, and A. Di Cristofano Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis Cancer Res., February 1, 2007; 67(3): 959 - 966. [Abstract] [Full Text] [PDF]

				G. Garcia-Rostan, A. M. Costa, I. Pereira-Castro, G. Salvatore, R. Hernandez, M. J.A. Hermsem, A. Herrero, A. Fusco, J. Cameselle-Teijeiro, and M. Santoro Mutation of the PIK3CA Gene in Anaplastic Thyroid Cancer Cancer Res., November 15, 2005; 65(22): 10199 - 10207. [Abstract] [Full Text] [PDF]