Down-regulation of type II L-thyroxine, 5'-monodeiodinase in cultured GC cells: different pathways of regulation by L-triiodothyronine and 3,3',5'-triiodo-L-thyronine.
The current consensus is that iodothyronines down-regulate type II T4 monodeiodinase (5'-DII) by an extranuclear acceleration of enzyme inactivation. We have investigated 5'-DII regulation in cultured GC cells, in which thyroid hormone responses are mediated by nuclear thyroid receptor (TR). GC cells actively converted T4 to T3, independent of propylthiouracil and with a Km of 1.4 nM, which are characteristics of 5'-DII. When GC cells were incubated with 10 nM T3, the Km was not affected. However, the maximum velocity was significantly down-regulated by 10 nM T3, from 0.15 to 0.018 pmol/mg protein.min. Dose-response studies showed that a 50% reduction in enzyme activity was achieved with either 0.25 nM T3 or 12 nM rT3. Time-course studies showed that a 50% reduction in enzyme activity occurred after 40 min of incubation with 100 nM rT3 and after 160 min of incubation with 10 nM T3. The down-regulation of 5'-DII by physiological concentrations of T3 has the characteristics of an effect that is mediated by nuclear TR. Our studies, therefore, suggest that down-regulation of 5'-DII by these iodothyronines in GC cells may occur by different mechanisms: enzyme inactivation for rT3, in agreement with the current consensus, and decreased enzyme production for T3, probably mediated by TR.
Halperin
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Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467.
Shapiro
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LE
Surks
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D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D007453:Iodide Peroxidase / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D007480:Iopanoic Acid / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D014284:Triiodothyronine / Q000494:pharmacology*; D014285:Triiodothyronine, Reverse / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D007480:Iopanoic Acid