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Regulation of Thyroid Transcription Factor-1 and Pax-8 in Rat Thyroid FRTL-5 Cells
Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Yamanashi 409-3898, Japan
Address all correspondence and requests for reprints to: Toshimasa Onaya, Professor and Chairman, Third Department of Internal Medicine, Yamanashi Medical University, 1110 Shimokato, Tamaho, Yamanashi 409-3898, Japan. E-mail: onayat{at}res.yamanashi-med.ac.jp
Tumor necrosis factor-
(TNF-) is known to modulate the expression
of thyroid-specific genes, such as thyroglobulin (TG), contributing to
the pathogenesis of autoimmune thyroid disease. In the present study,
we show that TNF- suppresses DNA-binding activity of thyroid
transcription factors, Pax-8 and thyroid transcription factor-1
(TTF-1), which is, in part, involved in TNF--induced decrease in TG
gene expression. Transfected into rat thyroid FRTL-5 cells, the
activity of reporter plasmid containing the rat TG promoter ligated to
a luciferase gene was significantly suppressed in the presence of
TNF-. In gel mobility shift analyses, protein-DNA complexes formed
by TTF-1 and Pax-8 were reduced when the nuclear extracts prepared from
TNF--treated FRTL-5 cells were used. The suppressive effect of
TNF- on TTF-1-DNA complex formation is, in part, caused by
suppression of TTF-1 gene transcription by TNF-. Expressions of
TTF-1 messenger RNA and protein, which were assessed by Northern blot
and Western blot analyses, respectively, were decreased by TNF-
treatment of FRTL-5 cells. In contrast, TNF- did not affect the
expression of Pax-8 messenger RNA. Treatment of FRTL-5 cells with
TNF- caused a decrease in Pax-8 protein in nuclear extracts and
accumulation of the protein in the cytoplasm, as assessed by Western
blot analyses. Mutation of the TTF-1/Pax-8-binding site lost the
TNF--induced decrease in TG promoter activity in a transfection
experiment. These results indicate that TNF- suppresses the activity
of TTF-1 and Pax-8 by different mechanisms, which, in part, seem to be
involved in TNF--induced decrease in TG gene expression.
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