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Third Department of Internal Medicine Yamanashi Medical University Tamaho, Yamanashi 409–38, Japan
The GA-binding protein (GABP), a transcription
factor with a widespread tissue distribution, consists of two subunits,
and ß1, and acts as a potent positive regulator of various genes.
The effect of GABP on transcription of the TSH receptor (TSHR) gene in
rat FRTL-5 thyroid cells has now been investigated. Both
deoxyribonuclease I footprint analysis and gel mobility-shift assays
indicated that bacterially expressed glutathione
S-transferase fusion proteins of GABP subunits bind to a
region spanning nucleotides (nt) -116 to -80 of the TSHR gene. In gel
mobility-shift assays, nuclear extracts of FRTL-5 cells and FRT cells
yielded several specific bands with a probe comprising nt -116 to
-80. Supershift assays with antibodies to GABP and to GABPß1
showed that GABP was a component of the probe complexes formed by the
nuclear extracts. Immunoblot analysis confirmed the presence of both
GABP subunits in the nuclear extracts. A reporter gene construct
containing the TSHR gene promoter was activated, in a dose-dependent
manner, in FRTL-5 cells by cotransfection with constructs encoding both
GABP and GABPß1. Both GABP binding to and activation of the TSHR
gene promoter were prevented by methylation of CpG sites at nt -93 and
-85.
These CpG sites were highly methylated (>82%) in FRT cells and completely demethylated in FRTL-5 cells, consistent with expression of the TSHR gene in the latter, but not the former. These results suggest that GABP regulates transcription of the TSHR gene in a methylation-dependent manner and that methylation of specific CpG sites and the methylation sensitivity of GABP contribute to the failure of FRT cells to express the endogenous TSHR gene.
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