Regulation of p27Kip1 protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells.
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.
Vitagliano
Donata
D
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.
Carlomagno
Francesca
F
Motti
Maria Letizia
ML
Viglietto
Giuseppe
G
Nikiforov
Yuri E
YE
Nikiforova
Marina N
MN
Hershman
Jerome M
JM
Ryan
Anderson J
AJ
Fusco
Alfredo
A
Melillo
Rosa Marina
RM
Santoro
Massimo
M
D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015321:Gene Rearrangement; D006801:Humans; D020935:MAP Kinase Signaling System; D009097:Multienzyme Complexes / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C452423:vandetanib