Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1)

F Trapasso; R Iuliano; A Boccia; A Stella; R Visconti; P Bruni; G Baldassarre; M Santoro; G Viglietto; A Fusco

doi:10.1128/MCB.20.24.9236-9246.2000

Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1)

Mol Cell Biol. 2000 Dec;20(24):9236-46. doi: 10.1128/MCB.20.24.9236-9246.2000.

Authors

F Trapasso¹, R Iuliano, A Boccia, A Stella, R Visconti, P Bruni, G Baldassarre, M Santoro, G Viglietto, A Fusco

Affiliation

¹ Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Università degli Studi di Catanzaro "Magna Graecia," 88100 Catanzaro," 80131 Naples, Italy.

Abstract

The r-PTPeta gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPeta (the human homolog of r-PTPeta) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPeta gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Ki oncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPeta caused G(1) growth arrest and increased the cyclin-dependent kinase inhibitor p27(Kip1) protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPeta tumor suppressor activity is mediated by p27(Kip1) protein stabilization, because suppression of p27(Kip1) protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPeta. Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed thyroid cells, the p27(Kip1) protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPeta regulated p27(Kip1) stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.

Publication types

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

MeSH terms

Animals
Blotting, Northern
Blotting, Western
Cell Cycle Proteins*
Cell Line
Cell Transformation, Neoplastic*
Cell Transformation, Viral*
Contact Inhibition
Cyclin-Dependent Kinase Inhibitor p27
Flow Cytometry
Genes, mos / genetics
Humans
Mice
Microscopy, Phase-Contrast
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism*
Mitogen-Activated Protein Kinases / metabolism
Oligonucleotides, Antisense / genetics
Oncogene Protein p21(ras) / genetics
Oncogene Protein p21(ras) / metabolism
Phenotype
Phosphorylation
Plasmids / genetics
Plasmids / metabolism
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / metabolism*
Rats
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Retroviridae / genetics
Retroviridae / physiology
Reverse Transcriptase Polymerase Chain Reaction
Thyroid Gland / cytology*
Thyroid Gland / pathology
Thyroid Neoplasms / enzymology
Thyroid Neoplasms / genetics
Transfection
Tumor Suppressor Proteins*

Substances

Cdkn1b protein, mouse
Cdkn1b protein, rat
Cell Cycle Proteins
Microtubule-Associated Proteins
Oligonucleotides, Antisense
Tumor Suppressor Proteins
Cyclin-Dependent Kinase Inhibitor p27
Mitogen-Activated Protein Kinases
PTPRJ protein, human
Protein Tyrosine Phosphatases
Ptprj protein, mouse
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Oncogene Protein p21(ras)