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RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho

Oncogene volume 20, pages 6973–6982 (2001)Cite this article

Abstract

Thyroid papillary carcinomas are characterized by RET/PTC rearrangements that cause the tyrosine kinase domain of the RET receptor to fuse with N-terminal sequences encoded by heterologous genes. This results in the aberrant expression of a ligand-independent and constitutively active RET kinase. We analysed actin reorganization induced by the RET/PTC1 oncogene in PC Cl 3 rat thyroid epithelial cells. Differently from oncogenes Src, Ras and Raf, RET/PTC1 caused actin filaments to form prominent stress fibers. Moreover, stress fibers were identified in human thyroid papillary carcinoma cell lines harboring RET/PTC1 rearrangements but not in thyroid carcinoma cells negative for RET/PTC rearrangements. RET/MEN 2A, a constitutively active but unrearranged membrane-bound RET oncoprotein, did not induce stress fibers in PC Cl 3 cells. Induction of stress fibers by RET/PTC1 was restricted to thyroid cells; it did not occur in NIH3T3 fibroblasts or MCF7 mammary cells. RET/PTC1-mediated stress fiber formation depended on Rho but not Rac small GTPase activity. In addition, inhibition of Rho, but not of Rac, caused apoptosis of RET/PTC1-expressing thyroid cells. We conclude that Rho is implicated in the actin reorganization and cell survival mediated by the chimeric RET/PTC1 oncogene in thyroid epithelial cells, both phenotypes being cell type- and oncogene type-specific.

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Acknowledgements

We gratefully acknowledge JA Fagin for the human thyroid cell lines, J Downward for the Rho/Rac constructs and purified proteins, F Basolo for the FB2 cells and D Salvatore for phosphorylation-specific anti-RET antibodies. We are grateful to JA Gilder for editing the text. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by the EC grant FIS5 1999 00032 and by the Progetto Biotecnologie ‘5%’ of the Consiglio Nazionale delle Ricerche (CNR). MV Barone was recipient of a scholarship of the Italian Foundation for Cancer Research (FIRC).

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Authors and Affiliations

  1. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Università di Napoli “Federico II”, via S. Pansini, Naples, 5, Italy

    Maria Vittoria Barone, Rosa Marina Melillo, Carmen Monaco, Maria Domenica Castellone, Alfredo Fusco & Massimo Santoro

  2. Fondazione Senatore Pascale, via M. Semmola, Naples, 80131, Italy

    Leandra Sepe, Alba Mineo & Giovanni Santelli

  3. Universita' del Sannio, via Port'Arsa 11, Benevento, 82100, Italy

    Donatella Tramontano

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  1. Maria Vittoria Barone
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  2. Leandra Sepe
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Correspondence to Massimo Santoro.

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Barone, M., Sepe, L., Melillo, R. et al. RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho. Oncogene 20, 6973–6982 (2001). https://doi.org/10.1038/sj.onc.1204886

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