(American Journal of Pathology. 2005;166:737-749.)
© 2005 American Society for Investigative Pathology
Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway
Regulation of p27kip1 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 p27kip1 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 p27kip1 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 p27kip1 mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27kip1 mislocalization in thyroid cancer cells occurred via phosphorylation of p27kip1 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 p27kip1 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 p27kip1 play major roles in thyroid carcinogenesis.
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Copyright © 2005 by the American Society for Investigative Pathology.
