Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells.
The ras family members and the tyrosine kinases RET and TRK are frequently activated in human tumors of the thyroid gland. To ascertain the effects of these oncogenes in cultured thyroid cells we have generated expression vectors containing activated versions of the three genes under the control of the thyroid-specific thyroglobulin gene promoter. Here we show that the expression of the three oncogenes differently affects thyroid differentiation. While the TRK-T1 oncogene interferes with the capability of thyroid cells of trapping iodide and only marginally affects thyroglobulin gene expression, both RET/PTC3 and N-ras(Gln61-Lys) induce a dramatic reduction of thyroglobulin mRNA and alleviate TSH dependency for cellular growth. However, none of the three oncogenes is able to induce the appearance of neoplastic transformation markers, such as growth in semisolid medium and tumorigenicity in athymic mice. This indicates that genetic events additional to TRK, RET, or N-ras activation are required for fully malignant transformation of thyroid cells.
Portella
G
G
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università Federico II, Naples, Italy. portella@unina.it
Vitagliano
D
D
Borselli
C
C
Melillo
R M
RM
Salvatore
D
D
Rothstein
J L
JL
Vecchio
G
G
Fusco
A
A
Santoro
M
M
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D002417:Cattle; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D011905:Genes, ras; D006801:Humans; D051379:Mice; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics*; D013961:Thyroid Gland / Q000166:cytology*; D014157:Transcription Factors; D014162:Transfection
D000943:Antigens, Differentiation; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C065400:oncogene protein trk; D013954:Thyroglobulin