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Oncogene Transformation of PC Cl3 Clonal Thyroid Cell Line Induces an Autonomous Pattern of Proliferation That Correlates with a Loss of Basal and Stimulated Phosphotyrosine Phosphatase Activity¹

Institute of Pharmacology, University of Genova School of Medicine; the Unit of Neuroscience, Advanced Biotechnology Center; and the Service of Pharmacology, National Institute for Cancer Research, Genova; the Department of Cellular and Molecular Biology and Pathology "L. Califano," University of Naples Federico II (M.T.B.), Naples; the Center of Endocrinology and Experimental Oncology, Consiglio Nazionale Delle Ricerche (S.S., MT.B.), Naples; and the Department of Clinical and Experimental Medicine, University of Reggio Calabria (A.F.), Catanzaro, Italy

Address all correspondence and requests for reprints to: Prof. Gennaro Schettini, Unit of Neuroscience, Advanced Biotechnology Center, National Institute for Cancer Research, Largo Rosanna Benzi 10, 16132 Genova, Italy. E-mail: schettini{at}sirio.cba.unige.it

The effects of the stable expression of E1A and/or middle T oncogenes on the proliferative activity of PC Cl3 normal thyroid cells are reported. The proliferation of PC Cl3 cells is mainly regulated by insulin and TSH in a stimulatory way and by somatostatin in an inhibitory fashion. The transformed cell lines, named PC Py and PC E1A Py, show an autonomous pattern of proliferation. The blockade of phosphotyrosine phosphatase activity with vanadate increased the proliferation rate of PC Cl3 under basal and stimulated conditions and completely prevented the inhibitory activity of somatostatin, suggesting that in PC Cl3 cells, a tonic tyrosine phosphatase activity regulates basal and stimulated proliferation, and that a somatostatin-dependent increase in this activity may represent a cytostatic signal. Conversely, in both PC Py and PC E1A Py, vanadate did not modify basal and stimulated proliferation. We analyzed tyrosine phosphatase activity in the different cell lines basally and under conditions leading to the arrest of cell proliferation: confluence (contact inhibition), growth factor deprivation (starvation), and somatostatin treatment. Under basal conditions, tyrosine phosphatase activity was significantly lower in PC Py and PC E1APy cell lines than that in the normal cells. The inhibition of the proliferation induced by contact inhibition or somatostatin treatment was accompanied by an increase in tyrosine phosphatase activity only in PC Cl3 cells. The reduction in tyrosine phosphatase activity in PC E1APy cells correlated with a significant reduction in the expression of R-PTP, a tyrosine phosphatase cloned from PC Cl3 cells. Conversely, the expression of another receptor-like PTP, PTPµ, was unchanged. Thus, PTP may be a candidate to mediate inhibitory signals (i.e. activation of somatostatin receptors or cell to cell contact) on the proliferative activity of PC Cl3 cells, and the reduction of its expression in the transformed cell lines may lead to an alteration in the control of cell proliferation.

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