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Essential Role of GATA2 in the Negative Regulation of Thyrotropin ß Gene by Thyroid Hormone and Its Receptors

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan

Address all correspondence and requests for reprints to: Shigekazu Sasaki, Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1–20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan. E-mail: sasakis{at}hama-med.ac.jp.

Previously we reported that the negative regulation of the TSHß gene by T₃ and its receptor [thyroid hormone receptor (TR)] is observed in CV1 cells when GATA2 and Pit1 are introduced. Using this system, we further studied the mechanism of TSHß inhibition. The negative regulatory element (NRE), which had been reported to mediate T₃-bound TR (T₃-TR)-dependent inhibition, is dispensable, because deletion or mutation of NRE did not impair suppression. The reporter construct, TSHß-D4-chloramphenicol acetyltransferase, which possesses only the binding sites for Pit1 and GATA2, was activated by GATA2 alone, and this transactivation was specifically inhibited by T₃-TR. The Zn finger region of GATA2 interacts with the DNA-binding domain of TR in a T₃-independent manner. The suppression by T₃-TR was impaired by overexpression of a dominant-negative type TR-associated protein (TRAP) 220, an N- and C-terminal deletion construct, indicating the participation of TRAP220. Chromatin immunoprecipitation assays with a thyrotroph cell line, TT1, revealed that T₃ treatment recruited histone deacetylase 3, reduced the acetylation of histone H4, and caused the dissociation of TRAP220 within 15–30 min. The reduction of histone H4 acetylation was transient, whereas the dissociation of TRAP220 persisted for a longer period. In the negative regulation of the TSHß gene by T₃-TR we report that 1) GATA2 is the major transcriptional activator of the TSHß gene, 2) the putative NRE previously reported is not required, 3) TR-DNA-binding domain directly interacts with the Zn finger region of GATA2, and 4) histone deacetylation and TRAP220 dissociation are important.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  RARα  |  VDR

Coregulators:   TRAP220

Ligands:   Thyroid hormone

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