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Transforming Growth Factor-ß1 Down-Regulation of Major Histocompatibility Complex Class I in Thyrocytes: Coordinate Regulation Of Two Separate Elements by Thyroid-Specific as Well as Ubiquitous Transcription Factors

Chair of Endocrinology (G.N., V.M., C.G., S.D.V., I.B., V.T., G.L., F.M.) Department of Medicine and Department of Oncology and Neuroscience (G.C.) University "G. D’Annunzio", Chieti, Italy 66100
Department of Experimental Medicine and Pathology (A.C.) University "La Spienza", Rome, Italy 00161
Experimental Immunology Branch (D.S.S.) National Cancer Institute and Metabolic Diseases Branch (M.N., L.D.K.) National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland 20892-1800

Transforming growth factor (TGF)-ß1-decreased major histocompatibility complex (MHC) class I gene expression in thyrocytes is transcriptional; it involves trans factors and cis elements important for hormone- as well as iodide-regulated thyroid growth and function. Thus, in rat FRTL-5 thyrocytes, TGF-ß1 regulates two elements within -203 bp of the transcription start site of the MHC class I 5'-flanking region: Enhancer A, -180 to -170 bp, and a downstream regulatory element (DRE), -127 to -90 bp, that contains a cAMP response element (CRE)-like sequence. TGF-ß1 reduces the interaction of a NF-B p50/fra-2 heterodimer (MOD-1) with Enhancer A while increasing its interaction with a NF-B p50/p65 heterodimer. Both reduced MOD-1 and increased p50/p65 suppresses class I expression. Decreased MOD-1 and increased p50/p65 have been separately associated with the ability of autoregulatory (high) concentrations of iodide to suppress thyrocyte growth and function, as well as MHC class I expression. TGF-ß1 has two effects on the downstream regulatory element (DRE). It increases DRE binding of a ubiquitously expressed Y-box protein, termed TSEP-1 (TSHR suppressor element binding protein-1) in rat thyroid cells; TSEP-1 has been shown separately to be an important suppressor of the TSH receptor (TSHR) in addition to MHC class I and class II expression. It also decreases the binding of a thyroid-specific trans factor, thyroid transcription factor-1 (TTF-1), to the DRE, reflecting the ability of TGF-ß1 to decrease TTF-1 RNA levels. TGF-ß1-decreased TTF-1 expression accounts in part for TGF-ß1-decreased thyroid growth and function, since decreased TTF-1 has been shown to decrease thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR gene expression, coincident with decreased MHC class I. Finally, we show that TGF-ß1 increases c-jun RNA levels and induces the formation of new complexes involving c-jun, fra-2, ATF-1, and c-fos, which react with Enhancer A and the DRE. TGF-ß1 effects on c-jun may be a pivotal fulcrum in the hitherto unrecognized coordinate regulation of Enhancer A and the DRE.

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