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oai:repisalud.isciii.es:20.500.12105/272132026-02-07T01:20:05Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Chiappetta, Gennaro author De Marco, Carmela author Quintiero, Alfina author Califano, Daniela author Gherardi, Simona author Malanga, Donatella author Scrima, Marianna author Montero-Conde, Cristina author Cito, Letizia author Monaco, Mario author Motti, Maria Letizia author Pasquinelli, Rosa author Agosti, Valter author Robledo, Mercedes author Fusco, Alfredo author Viglietto, Giuseppe author Montero-Conde, Cristina author 2007-06 Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1-Cullin-F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours. Immunohistochemistry analysis showed that Skp2 was overexpressed significantly in thyroid carcinomas (26 out of 51) compared with goitres (0 out of 12, P<0.001) or adenomas (1 out of 10, P<0.05), and that high Skp2 expression was detected more often in anaplastic thyroid (ATC; 83%, n=12) than follicular thyroid (FTC; 40%, n=20) or papillary thyroid (PTC; 42%, n=19) carcinomas (P<0.05). Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05). In most cases, the observed overexpression of Skp2 protein was paralleled by an increase in the levels of Skp2 mRNA, and we observed Skp2 gene amplification at 5p13 in 2 out of 6 cell lines and in 9 out of 23 primary tumours (six out of eight ATCs, two out of nine PTCs and one out of six FTCs) using Q-PCR and/or fluorescence in situ hybridization analysis. Finally, in vitro experiments demonstrated that suppression of Skp2 expression drastically reduced proliferation of thyroid cancer cells and, conversely, forced expression of Skp2 circumvented serum dependency and contact inhibition in Skp2-negative cells by promoting p27 degradation. These findings indicate that Skp2 plays an important role for the development of thyroid cancer. Endocr Relat Cancer . 2007 Jun;14(2):405-20. ENDOCRINE-RELATED CANCER 17639054 https://hdl.handle.net/20.500.12105/27213 CARCINOMA CELL-LINE GASE SUBUNIT SKP2 F-BOX PROTEIN INTERACTING PROTEIN-2 P27(KIP1) EXPRESSION GENE-EXPRESSION POOR-PROGNOSIS INHIBITOR P27 GROWTH DEGRADATION Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer.