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Molecular and Cellular Biology, December 2000, p. 9236-9246, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Rat Protein Tyrosine Phosphatase eta  Suppresses the Neoplastic Phenotype of Retrovirally Transformed Thyroid Cells through the Stabilization of p27Kip1

Francesco Trapasso,1 Rodolfo Iuliano,1 Angelo Boccia,2 Antonella Stella,1 Roberta Visconti,3 Paola Bruni,2 Gustavo Baldassarre,2 Massimo Santoro,3 Giuseppe Viglietto,2 and Alfredo Fusco*,1

Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Università degli Studi di Catanzaro "Magna Graecia," 88100 Catanzaro,1 and Istituto dei Tumori di Napoli2 and Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II,"3 80131 Naples, Italy

Received 15 March 2000/Returned for modification 13 June 2000/Accepted 27 September 2000

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 G1 growth arrest and increased the cyclin-dependent kinase inhibitor p27Kip1 protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPeta tumor suppressor activity is mediated by p27Kip1 protein stabilization, because suppression of p27Kip1 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 p27Kip1 protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPeta regulated p27Kip1 stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.


* Corresponding author. Mailing address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II," via Pansini 5, 80131 Naples, Italy. Phone: 39 081 7463056. Fax: 39 081 7463037. E-mail: afusco{at}napoli.com.


Molecular and Cellular Biology, December 2000, p. 9236-9246, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



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