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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

DOI

10.1158/0008-5472.CAN-03-3918

Type

Journal article

Journal

Cancer Res

Publication Date

01/06/2004

Volume

64

Pages

3823 - 3829

Keywords

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