Thyroid-stimulating hormone and insulin-like growth factor-1 synergize to elevate 1,2-diacylglycerol in rat thyroid cells. Stimulation of DNA synthesis via interaction between lipid and adenylyl cyclase signal transduction systems.
Thyroid-stimulating hormone (TSH) and insulin-like growth factor-1 (IGF-1) synergistically stimulate DNA synthesis in thyroid cells. In this report, a novel mechanism for mediation of this synergistic interaction is described in rat thyroid (FRTL-5) cells. Because phorbol myristate acetate stimulates DNA synthesis, the effects of TSH, IGF-1 and insulin on FRTL-5 cell content of 1,2-diacylglycerol (1,2-DG), the endogenous activator of protein kinase C, were measured. After 6 d, TSH, IGF-1 and insulin caused increases in cellular 1,2-DG (mean +/- SE) to 180 +/- 10%, 540 +/- 50%, and 360 +/- 40% of control, respectively, whereas TSH plus IGF-1 and TSH plus insulin synergistically increased 1,2-DG to 1,890 +/- 310% and 1,690 +/- 230%, respectively. In the absence of insulin, the effect of TSH to elevate 1,2-DG exhibited an EC50 of approximately 2,000 microU/ml. The synergistic interaction of insulin and TSH was found to increase the potency of TSH by 300-fold (EC50 was approximately 7 microU/ml) in addition to increasing the efficacy of TSH. The effect of TSH appeared to be mediated by TSH-stimulated increases in cyclic AMP (cAMP). Forskolin and 8-bromo-cAMP, like TSH, caused modest increases in 1,2-DG and DNA synthesis, whereas forskolin plus insulin and 8-bromo-cAMP plus insulin markedly elevated 1,2-DG content and stimulated DNA synthesis. Under all conditions, increases in 1,2-DG content correlated with stimulation of DNA synthesis. These findings suggest that the synergistic stimulation of DNA synthesis in thyroid cells by TSH, via cAMP, and IGF-1 is mediated by 1,2-DG. Moreover, they implicate a novel interaction between the lipid and adenylyl cyclase signaling systems for the regulation of cell proliferation.
Brenner-Gati
L
L
Department of Medicine, Cornell University Medical College, New York 10021.
Berg
K A
KA
Gershengorn
M C
MC
D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D004247:DNA / Q000096:biosynthesis*; D004075:Diglycerides / Q000096:biosynthesis*; D004357:Drug Synergism; D005989:Glycerides / Q000096:biosynthesis*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008055:Lipids / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013002:Somatomedins / Q000494:pharmacology*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology*
C011439:1,2-diacylglycerol; D004075:Diglycerides; D005989:Glycerides; D008055:Lipids; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D004247:DNA; D000242:Cyclic AMP; D011493:Protein Kinase C; D000262:Adenylyl Cyclases