1. RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho.
- Author
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Barone MV, Sepe L, Melillo RM, Mineo A, Santelli G, Monaco C, Castellone MD, Tramontano D, Fusco A, and Santoro M
- Subjects
- 3T3 Cells, Actins metabolism, Adenocarcinoma pathology, Animals, Apoptosis, Breast Neoplasms pathology, Cell Line, Cell Line, Transformed, Cell Survival, DNA Replication, Dimerization, Female, Humans, MAP Kinase Signaling System, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Multiple Endocrine Neoplasia Type 2a genetics, Multiple Endocrine Neoplasia Type 2a metabolism, Neoplasm Invasiveness, Neoplasm Proteins metabolism, Organ Specificity, Phenotype, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Rats, Receptor Protein-Tyrosine Kinases, Recombinant Fusion Proteins physiology, Transfection, Tumor Cells, Cultured, Carcinoma, Papillary pathology, Drosophila Proteins, Oncogene Proteins, Fusion physiology, Signal Transduction physiology, Stress Fibers physiology, Thyroid Gland cytology, Thyroid Neoplasms pathology, rho GTP-Binding Proteins physiology
- 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.
- Published
- 2001
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