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Loss of p27 Expression Through RAS->BRAF->MAP Kinase-Dependent Pathway in Human Thyroid Carcinomas

Maria Letizia Motti, Carmela De Marco, Daniela Califano, Silvia De Gisi, Donatella Malanga, Giancarlo Troncone, Angela Persico, Simona Losito, Fernanda Fabiani, Massimo Santoro, Alfredo Fusco and Giuseppe Viglietto

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In the present study, we report that the RAS->BRAF->MAP kinase cascade plays a crucial role in the regulation of the Skp2/p27 pathway in thyroid cancer cells and that this is critical for cell proliferation. In vitro studies with cellular models of human thyroid carcinoma cells demonstrated that the adoptive expression of oncogenic RET/PTC1, Ha-RASV12 or BRAFV600E enhances Skp2 and reduces p27 protein expression in a MAP kinase-dependent manner; that RAS->BRAF->MAP kinase–dependent control of p27 expression in thyroid cancer cells occurs by regulating the stability of Skp2 and p27 protein; and that antisense oligonucleotides to p27 suppress growth arrest induced by MEK inhibitors. Finally, analysis of human thyroid carcinomas indicated that MAP kinase-positive thyroid tumours—as detected by immunostaining for p-ERK—presented high p27 degradative activity and low levels of p27 protein (N=30; P<0.05). In summary, our results indicate that constitutive signalling of the MAP kinase cascade contributes to the development of thyroid cancer promoted by activated RAS and BRAF oncogenes and that this occurs, at least in part, by compromising the inhibitory function of p27.

Authors

Maria Letizia Motti

Università Parthenope; Napoli, Italy

Carmela De Marco

Università Federico II; Napoli, Italy

Daniela Califano

Università Federico II; Napoli, Italy

Silvia De Gisi

Università Magna Graecia; Catanzaro, Italy

Donatella Malanga

Università Magna Graecia; Catanzaro, Italy

Giancarlo Troncone

Università Federico II; Napoli, Italy

Angela Persico

Istituto Nazionale Tumori; Napoli, Italy

Simona Losito

Istituto Nazionale Tumori; Napoli, Italy

Fernanda Fabiani

Università Magna Graecia; Catanzaro, Italy

Massimo Santoro

Università Federico II; Napoli, Italy

Alfredo Fusco

Università Federico II; Napoli, Italy

Giuseppe Viglietto

Università Magna Graecia; Catanzaro, Italy

Purchase article for $19

Subscribe to this journal for $129/year