Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1).
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.
Trapasso
F
F
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.
Iuliano
R
R
Boccia
A
A
Stella
A
A
Visconti
R
R
Bruni
P
P
Baldassarre
G
G
Santoro
M
M
Viglietto
G
G
Fusco
A
A
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D003260:Contact Inhibition; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005434:Flow Cytometry; D016258:Genes, mos / Q000235:genetics; D006801:Humans; D051379:Mice; D008858:Microscopy, Phase-Contrast; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000166:cytology* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020928:Mitogen-Activated Protein Kinases; C486288:PTPRJ protein, human; D017027:Protein Tyrosine Phosphatases; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D015689:Oncogene Protein p21(ras)