The Mechanism of Negative Transcriptional Regulation by Thyroid Hormone: Lessons From the Thyrotropin β Subunit Gene

Sasaki, Shigekazu; Matsushita, Akio; Kuroda, Go; Nakamura, Hiroko; Osuga, Yutaka; Suda, Takafumi

doi:10.1016/bs.vh.2017.06.006

Cited by 14 publications

(19 citation statements)

References 146 publications

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“…Since repression of the prepro-TRH gene by T3 is ameliorated in TRβ2-knockout (KO) mice, TRβ2 is thought to mediate the negative regulation of this gene by T3 [7]. However, the mechanism by which the liganded TRβ2 inhibits prepro-TRH expression still remains unclear [1,8].…”

Section: Introductionmentioning

confidence: 99%

“…-52 in rat) and is highly conserved among species [16]. Although many investigators have accepted the physiological relevance of the site 4 [2][3][4][17][18][19], the nTRE-based model raises some critical questions [8]. First, as Hollenberg described [1], it is difficult to explain how coactivators and/or co-repressors behave after T3 binding to TRβ2 on the nTRE.…”

Section: Introductionmentioning

confidence: 99%

“…However, the nTRE in the TSHβ genes [13] and site 4 [15] appear to be a single halfsite. If this is the case, the receptor specificity is difficult to explain [8]. Recent genome wide analysis rather suggested that the single halfsite may mediate positive regulation in combination with another halfsite located in a distal position [20].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, unliganded TRs are not the activator of the TSHβ gene. This implies that (i), at the molecular level, T3-dependent negative regulation is not a mirror image of the positive regulation [26], (ii) the presence of the nTRE should be re-examined, and (iii) the transcription of the TSHβ in thyrotroph is maintained by factor(s) other than unliganded TRs [8]. GATA2 and Pit1 are the transcription factors that determine thyrotroph differentiation in the anterior pituitary and activate the TSHβ promoter [27].…”

Section: Introductionmentioning

confidence: 99%

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G ATA2 mediates the negative regulation of the prepro-thyrotropin-releasing hormone gene by liganded T3 receptor β2 in the rat hypothalamic paraventricular nucleus

et al. 2020

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Thyroid hormone (T3) inhibits thyrotropin-releasing hormone (TRH) synthesis in the hypothalamic paraventricular nucleus (PVN). Although the T3 receptor (TR) β2 is known to mediate the negative regulation of the prepro-TRH gene, its molecular mechanism remains unknown. Our previous studies on the T3-dependent negative regulation of the thyrotropin β subunit (TSHβ) gene suggest that there is a tethering mechanism, whereby liganded TRβ2 interferes with the function of the transcription factor, GATA2, a critical activator of the TSHβ gene. Interestingly, the transcription factors Sim1 and Arnt2, the determinants of PVN differentiation in the hypothalamus, are reported to induce expression of TRβ2 and GATA2 in cultured neuronal cells. Here, we confirmed the expression of the GATA2 protein in the TRH neuron of the rat PVN using immunohistochemistry with an anti-GATA2 antibody. According to an experimental study from transgenic mice, a region of the rat prepro-TRH promoter from nt. -547 to nt. +84 was able to mediate its expression in the PVN. We constructed a chloramphenicol acetyltransferase (CAT) reporter gene containing this promoter sequence (rTRH(547)-CAT) and showed that GATA2 activated the promoter in monkey kidney-derived CV1 cells. Deletion and mutation analyses identified a functional GATA-responsive element (GATA-RE) between nt. -357 and nt. -352. When TRβ2 was co-expressed, T3 reduced GATA2-dependent promoter activity to approximately 30%. Unexpectedly, T3-dependent negative regulation was maintained after mutation of the reported negative T3-responsive element, site 4. T3 also inhibited the GATA2-dependent transcription enhanced by cAMP agonist, 8-bromo-cAMP. A rat thyroid medullary carcinoma cell line, CA77, is known to express the preproTRH mRNA. Using a chromatin immunoprecipitation assay with this cell line where GATA2 expression plasmid was transfected, we observed the recognition of the GATA-RE by GATA2. We also confirmed GATA2 binding using gel shift assay with the probe for the GATA-RE. In CA77 cells, the activity of rTRH(547)-CAT was potentiated by overexpression of GATA2, and it was inhibited in a T3-dependent manner. These results suggest that GATA2 transactivates the rat prepro-TRH gene and that liganded TRβ2 interferes with this activation via a tethering mechanism as in the case of the TSHβ gene.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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G ATA2 mediates the negative regulation of the prepro-thyrotropin-releasing hormone gene by liganded T3 receptor β2 in the rat hypothalamic paraventricular nucleus

et al. 2020

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“…The latter determines the hormonal specificity of TSH. As in the case of prepro-TRH gene, both genes are negatively regulated by liganded TR [8]. For TSHβ genes, the presence of the negative TRE (nTRE) has been postulated as a counterpart of TREs in positively regulated genes [6].…”

Section: Introductionmentioning

confidence: 99%

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Multifactorial Regulation of the Activity of Hypophysiotropic Thyrotropin-Releasing Hormone Neurons

Joseph‐Bravo

Jaimes-Hoy

Rodríguez-Rodríguez

et al. 2021

Masterclass in Neuroendocrinology

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The Mechanism of Negative Transcriptional Regulation by Thyroid Hormone: Lessons From the Thyrotropin β Subunit Gene

Cited by 14 publications

References 146 publications

G ATA2 mediates the negative regulation of the prepro-thyrotropin-releasing hormone gene by liganded T3 receptor β2 in the rat hypothalamic paraventricular nucleus

G ATA2 mediates the negative regulation of the prepro-thyrotropin-releasing hormone gene by liganded T3 receptor β2 in the rat hypothalamic paraventricular nucleus

Untitled

Multifactorial Regulation of the Activity of Hypophysiotropic Thyrotropin-Releasing Hormone Neurons

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