Loss of p27 expression through RAS-->BRAF-->MAP kinase-dependent pathway in human thyroid carcinomas.
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.
Motti
Maria Letizia
ML
Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali, Università Parthenope, Napoli, Italy.
De Marco
Carmela
C
Califano
Daniela
D
De Gisi
Silvia
S
Malanga
Donatella
D
Troncone
Giancarlo
G
Persico
Angela
A
Losito
Simona
S
Fabiani
Fernanda
F
Santoro
Massimo
M
Chiappetta
Gennaro
G
Fusco
Alfredo
A
Viglietto
Giuseppe
G
D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D050760:Cyclin-Dependent Kinase Inhibitor p27; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases