Control of c-fos and c-myc proto-oncogene induction in rat thyroid cells in culture.
Removal of TSH, insulin, and cortisol from the medium, and decreasing the serum content to 0.2%, abolishes both the proliferate and differentiated state of FRTL-5 rat thyroid cells in culture. In these basal conditions, the individual addition of TSH, insulin, insulin-like growth factor-I (IGF-I), phorbol 12-myristate 13-acetate (TPA), alpha 1-adrenergic agents, or A23187, increase c-myc and/or c-fos proto-oncogene expression. Under the same conditions, only the addition of TSH increased cAMP levels; 8-bromo-cAMP can increase c-myc or c-fos mRNA levels. Pretreatment of cells with phorbol 12,13-dibutyrate, an agent which down regulates the C-kinase, completely inhibits the effect of TPA on proto-oncogene expression but has no affect on the A23187 induced-increase. The sum of these results indicate that at least four separate signal systems independently increase c-myc or c-fos gene expression in FRTL-5 cells cAMP (TSH), C-kinase (TPA), Ca++/phosphoinositide (A23187), and that influenced by insulin/IGF-I. None of the ligands, when individually returned to cells in basal medium (no TSH, insulin, or cortisol and only 0.2% serum), increases cell number; norepinephrine, and A23187 do not increase [3H]thymidine incorporation into DNA under these conditions; and combinations of the ligands can be more than additive in effecting [3H]thymidine incorporation into DNA but are only additive in effecting proto-oncogene expression. Insulin/IGF-I plus TSH or insulin/IGF-I plus norepinephrine can increase both proto-oncogene expression and [3H]thymidine incorporation into DNA to the same extent; however, the former combination can increase cell number whereas the latter cannot. There is therefore no simple correlation between the ability of the above ligands to increase proto-oncogene expression and their ability to increase cell number or induce DNA synthesis. Under conditions where insulin and IGF-I increase proto-oncogene expression but not cell number, they can increase thyroglobulin gene expression. In the presence of TSH, insulin and IGF-I are not additive with each other in their ability to increase thyroglobulin or proto-oncogene gene expression but are additive in their ability to increase cell number. Proto-oncogene expression in FRTL-5 rat thyroid cells, as in other cell systems, may thus be related to functional as well as proliferative responses.
Isozaki
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Section on Cell Regulation, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Kohn
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LD
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013954:Thyroglobulin / Q000096:biosynthesis; D013961:Thyroid Gland / Q000166:cytology*; D013972:Thyrotropin / Q000494:pharmacology; D014316:Tritium
D007328:Insulin; D012333:RNA, Messenger; D014316:Tritium; D000001:Calcimycin; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D004247:DNA; D013954:Thyroglobulin; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine; D009638:Norepinephrine