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Control of c-fos and c-myc Proto-Oncogene Induction in Rat Thyroid Cells in Culture

Section on Cell Regulation, Laboratory of Biochemistry and Metabolism, National Instituteof Diabetes, Digestive and Kidney Diseases, National Institutes of Health Bethesda, Maryland 20892
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical School Tokyo 162, Japan

Address requests for reprints to: Leonard D. Kohn, Section on Cell Regulation, Laboratory of Biochemistry and Metabolism, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.

Abstract

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), 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-bromocAMP 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 inducedincrease. 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 protooncogene 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.

Received for publication August 3, 1987. Accepted for publication September 14, 1987.

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