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We show that treatment of a panel of thyroid carcinoma cell lines naturally harboring the RET/PTC1 oncogene, with the RET kinase inhibitors PP1 and ZD6474, results in reversible G(1) arrest. This is accompanied by interruption of Shc and mitogen-activated protein kinase (MAPK) phosphorylation, reduced levels of G(1) cyclins, and increased levels of the cyclin-dependent kinase inhibitor p27Kip1 because of a reduced protein turnover. MAP/extracellular signal-regulated kinase 1/2 inhibition by U0126 caused G(1) cyclins down-regulation and p27Kip1 up-regulation as well. Forced expression of RET/PTC in normal thyroid follicular cells caused a MAPK- and proteasome-dependent down-regulation of p27Kip1. Reduction of p27Kip1 protein levels by antisense oligonucleotides abrogated the G(1) arrest induced by RET/PTC blockade. Therefore, in thyroid cancer, RET/PTC-mediated MAPK activation contributes to p27Kip1 deregulation. This pathway is implicated in cell cycle progression and in response to small molecule kinase inhibitors.

Original publication




Journal article


Cancer Res

Publication Date





3823 - 3829


Cell Cycle Proteins, Cell Line, Tumor, Cyclin D, Cyclin E, Cyclin-Dependent Kinase Inhibitor p27, Cyclins, Cysteine Endopeptidases, Enzyme Inhibitors, Gene Rearrangement, Humans, MAP Kinase Signaling System, Multienzyme Complexes, Oncogene Proteins, Fusion, Piperidines, Proteasome Endopeptidase Complex, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Pyrazoles, Pyrimidines, Quinazolines, Receptor Protein-Tyrosine Kinases, Thyroid Neoplasms, Tumor Suppressor Proteins, Up-Regulation