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, Gennaro Chiappetta, Alfredo Fusco, Giuseppe Viglietto

Research output: Contribution to journalArticle

Abstract

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 tumors - 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.

Original languageEnglish
Pages (from-to)2817-2825
Number of pages9
JournalCell Cycle
Volume6
Issue number22
Publication statusPublished - Nov 15 2007

Keywords

  • MAP kinase
  • Oncogene
  • p27
  • SKP2
  • Thyroid cancer

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

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