Regulation of p27Kip1 protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells

Donata Vitagliano; Francesca Carlomagno; Maria Letizia Motti; Giuseppe Viglietto; Yuri E Nikiforov; Marina N Nikiforova; Jerome M Hershman; Anderson J Ryan; Alfredo Fusco; Rosa Marina Melillo; Massimo Santoro

doi:10.1158/0008-5472.CAN-03-3918

Regulation of p27Kip1 protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells

Cancer Res. 2004 Jun 1;64(11):3823-9. doi: 10.1158/0008-5472.CAN-03-3918.

Authors

Donata Vitagliano¹, Francesca Carlomagno, Maria Letizia Motti, Giuseppe Viglietto, Yuri E Nikiforov, Marina N Nikiforova, Jerome M Hershman, Anderson J Ryan, Alfredo Fusco, Rosa Marina Melillo, Massimo Santoro

Affiliation

¹ Dipartimento di Biologia e Patologia Cellulare e Molecolare, University 'Federico II' c/o Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Naples, Italy.

PMID: 15172989
DOI: 10.1158/0008-5472.CAN-03-3918

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
Cell Cycle Proteins
Cyclin D
Cyclin E
Cyclins
Enzyme Inhibitors
Multienzyme Complexes
Oncogene Proteins, Fusion
Piperidines
Proto-Oncogene Proteins
Pyrazoles
Pyrimidines
Quinazolines
Tumor Suppressor Proteins
Cyclin-Dependent Kinase Inhibitor p27
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
ret-PTC fusion oncoproteins, human
Cysteine Endopeptidases
Proteasome Endopeptidase Complex
vandetanib