RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho.
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.
Barone
M V
MV
Centro 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.
Sepe
L
L
Melillo
R M
RM
Mineo
A
A
Santelli
G
G
Monaco
C
C
Castellone
M D
MD
Tramontano
D
D
Fusco
A
A
Santoro
M
M
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002291:Carcinoma, Papillary / Q000473:pathology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival; D004261:DNA Replication; D019281:Dimerization; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D009928:Organ Specificity; D010641:Phenotype; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D022502:Stress Fibers / Q000502:physiology*; D013961:Thyroid Gland / Q000166:cytology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D000199:Actins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat; C093573:ret-PTC fusion oncoproteins, human; D020741:rho GTP-Binding Proteins