We will continue to study the rat bearing the transplantable Walker 256 carcinoma (T) with decreased serum T4 and T3 but normal TSH as a model for patients with nonthyroidal disease who have decreased serum T3. We propose to determine whether the previously described decrease in hepatic nuclear T3 receptors reflects a specific or general change in nonhistone protein synthesis, whether other aspects of hepatic protein synthesis are altered in T rats and whether anterior pituitary nuclear T3 receptor and GH content are changed in these animals. We will characterize the dose-response curve for pituitary GH content in relation to the saturation of pituitary nuclear receptors. Hepatic nuclear T3 receptor forms will be characterized by means of a T3 photoaffinity probe and the t 1/2 of receptor will be determined. The response of the thyroid to endogenous TSH will also be measured. Additional studies will examine the influence of nonthyroidal disease on experimental thyrotoxicosis. Walker 256 carcinoma and experimental laparotomy will be used in rats with acute and chronic experimental thyrotoxicosis. Biological responses to T3 such as hepatic-glycerophosphate dehydrogenase and malic enzyme activity and pituitary GH content will be assessed. We propose to study further tumor products in serum from T rats and conditioned medium from cultured cloned Walker 256 carcinoma which decrease nuclear T3 receptor levels in cultured GC cells. Tumor product effects on receptor synthesis and turnover in GC cells, on receptor synthesis in relation to GC cell nonhistone protein synthesis, and on T3 action (receptor depletion, GH induction, growth, amino acid transport will be examined. Lastly, we will continue to study the interaction between 5,5'-diphenylhydantoin (DPH) and the thyroid hormone system. We will explore the possible use of DPH in experimental thyrotoxicosis and we will test the effect of DPH on the rate of growth and GH production of GC cell tumors transplanted subcutaneously in rats.

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National Cancer Institute (NCI)
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Endocrinology Study Section (END)
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Montefiore Medical Center (Bronx, NY)
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Halperin, Y; Shapiro, L E; Surks, M I (1994) 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. Endocrinology 135:1464-9
Hupart, K H; Hodin, R A; Lazar, M A et al. (1993) c-erb-A mRNA correlates with T3-receptor levels in liver and pituitary of tumor rats. Thyroid 3:55-8
Mokshagundam, S; Shapiro, L E; Surks, M I (1992) Heat stress of cultured GC cells enhances triiodothyronine-induced growth hormone production by action within the 5'-flanking region of the rat growth hormone gene. Biochem Biophys Res Commun 188:638-43
Reynolds, A M; Surks, M I; Shapiro, L E (1991) The effects of chronic exposure to supraphysiological concentrations of 3, 5, 3' triiodo-L-thyronine (T3) on cultured GC cells. J Cell Physiol 149:544-7
Halperin, Y; Shapiro, L E; Surks, M I (1991) Role of L-thyroxine in nuclear thyroid hormone receptor occupancy and growth hormone production in cultured GC cells. J Clin Invest 88:1291-9
Ramirez, I J; Halwer, M; Shapiro, L E et al. (1991) Zinc(II) inhibits the release of thyroid and glucocorticoid receptors from chromatin of cultured GC cells. Horm Metab Res 23:155-61
Hupart, K H; DeFesi, C R; Katz, C P et al. (1990) Differential response to L-triiodothyronine of anterior pituitary growth hormone messenger ribonucleic acid (mRNA) and beta-thyrotropin mRNA in a hypothyroid Walker 256 carcinoma-bearing rat model of nonthyroidal disease. Endocrinology 126:616-21
Khawaja, Y; Dobnig, H; Shapiro, L E et al. (1990) Increase in hepatic mitochondrial alpha-glycerophosphate dehydrogenase activity after surgical stress in hyperthyroid rats. Endocrinology 127:387-93
Surks, M I; Ramirez, I J; Shapiro, L E et al. (1989) Effect of zinc(II) and other divalent cations on binding of 3,5,3'-triiodo-L-thyronine to nuclear receptors from cultured GC cells. J Biol Chem 264:9820-6
Shapiro, L E; Katz, C P; DeFesi, C R et al. (1989) Heat shock of cultured GC cells enhances the level of triiodothyronine induced growth hormone (GH) and GH messenger ribonucleic acid. Endocrinology 125:180-5

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