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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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