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RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho
M V Barone1, L Sepe, R M Melillo
1Centro di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II", via S. Pansini 5, Naples, Italy.
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.
Insights
Thyroid papillary carcinomas with RET/PTC1 rearrangements induce stress fibers via Rho GTPase activity. This actin reorganization is specific to thyroid cells and linked to cell survival.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Thyroid papillary carcinomas often feature RET/PTC rearrangements, leading to constitutively active RET kinase.
- The RET/PTC1 oncogene's role in cellular actin organization is not fully understood.
Purpose of the Study:
- To investigate the effects of the RET/PTC1 oncogene on actin reorganization in thyroid epithelial cells.
- To determine the specific signaling pathways and cell types involved in RET/PTC1-induced actin changes and their impact on cell survival.
Main Methods:
- Analysis of actin stress fiber formation in PC Cl 3 rat thyroid epithelial cells expressing RET/PTC1.
- Comparison with other oncogenes (Src, Ras, Raf) and RET variants (RET/MEN 2A).
- Assessment of RET/PTC1-induced effects in different cell lines (human thyroid carcinoma, NIH3T3 fibroblasts, MCF7 mammary cells) and the role of Rho and Rac GTPases.
Main Results:
- RET/PTC1 oncogene specifically induced prominent actin stress fibers in thyroid cells, unlike other oncogenes.
- Stress fibers were observed in human thyroid papillary carcinoma cells with RET/PTC1 rearrangements.
- RET/PTC1-mediated stress fiber formation and cell survival were dependent on Rho GTPase activity, but not Rac, and were cell type-specific.
Conclusions:
- The chimeric RET/PTC1 oncogene drives unique actin reorganization and promotes thyroid cell survival through Rho GTPase signaling.
- These findings highlight the cell type- and oncogene-specific roles of Rho in mediating RET/PTC1 effects in thyroid cancer.