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

The r-PTP eta 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/HPTP eta (the hum an homolog of r-PTP eta) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTP eta gene in highl y malignant rat thyroid cells transformed by retroviruses carrying the v-mo s and v-ms-Ki oncogenes suppresses their malignant phenotype. Cell cycle an alysis demonstrated that r-PTP eta caused G(1) growth arrest and increased the cyclin-dependent kinase inhibitor p27(Kip1) protein level by reducing t he proteasome-dependent degradation rate. We propose that the r-PTP eta tum or suppressor activity is mediated by p27(Kip1) protein stabilization, beca use suppression of p27(Kip1) protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTP eta , Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed t hyroid cells, the p27(Kip1) protein level was regulated by the mitogen-acti vated protein (MAP) kinase pathway and that r-PTP eta regulated p27(Kip1) s tability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.