Thyrotrope Expression and Thyroid Hormone Inhibition Map to Different Regions of the Mouse Glycoprotein Hormone α-Subunit Gene Promoter*

Sarapura, Virginia D.; Wood, William M.; Gordon, David F.; Ocran, K; Kao, M; Ridgway, E. Chester

doi:10.1210/endo-127-3-1352

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…Expression was substantially decreased by truncation from -257 to -240 and from -240 to -206. Thus, the regions important for expression of the human and mouse genes in aoT3-1 cells show some overlap with each other and with those required for expression of the mouse gene in thyrotrope tumor cells, which were mapped from -480 to -417 and -254 to -177 by using a different set of truncation end points (39,42 Further upstream (using a probe -442 to -151), multiple footprints within the region from -382 to -244 became evident (Fig. 3).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, the equine gene carries no TSE or CRE, though it does contain two GATA elements that bind the protein ot-ACT from placental cells (49), while the mouse gene has no TSE, CREs, or GATA elements, consistent with its lack of expression in placental cells. In thyrotrope tumor cells, expression of the mouse a-subunit gene appears to be conferred by two large proximal regions which are bound by tissue-specific proteins (39,42).…”

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confidence: 99%

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Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein.

Horn¹,

Windle²,

Barnhart³

et al. 1992

Mol. Cell. Biol.

120

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The molecular mechanisms for the development of multiple distinct endocrine cell types in the anterior pituitary have been an area of intensive investigation. Though the homeodomain protein Pit-1/GHF-1 is known to be involved in differentiation of the somatotrope and lactotrope lineages, which produce growth hormone and prolactin, respectively, little is known of the transcriptional regulators important for the gonadotrope cell lineage, which produces the glycoprotein hormones luteinizing hormone and follicle-stimulating hormone. Using transgenic mice and transfection into a novel gonadotrope lineage cell line, we have identified a regulatory element that confers gonadotrope-specific expression to the glycoprotein hormone a-subunit gene.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein.

Horn¹,

Windle²,

Barnhart³

et al. 1992

Mol. Cell. Biol.

120

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“…Several of the best-studied examples involve genes in the hypothalamic-pituitary-thyroid axis that are subject to feedback inhibition by T3. These include the hypothalamic thyrotropin-releasing hormone (TRH) gene (17,20) and the pituitary thyroid-stimulating hormone ␣-subunit (TSH␣) (8,27) and TSH␤ (5,7,37,39) genes. In general, negative regulation has been localized to the proximal regions of these promoters.…”

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confidence: 99%

Nuclear Receptor Corepressors Activate Rather than Suppress Basal Transcription of Genes That Are Negatively Regulated by Thyroid Hormone

Tagami

Madison

Nagaya

et al. 1997

Molecular and Cellular Biology

186

118

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A group of transcriptional cofactors referred to as corepressors (CoRs) were recently shown to play a central role in basal silencing of genes that contain positive triiodothyronine (T3) response elements. In a reciprocal manner, negatively regulated genes are stimulated by unliganded thyroid hormone receptor (TR) and repressed upon the addition of T3. We used a TR␤ mutant, called P214R, which fails to interact with CoRs, to examine whether CoRs also play a role in the control of genes that are negatively regulated in response to T3. In studies of three negatively regulated genes (the pituitary thyroid-stimulating hormone ␣-subunit [TSH␣], TSH␤, and hypothalamic thyrotropin-releasing hormone [TRH] genes), stimulation of basal promoter activity by unliganded TR␤ was impaired by introducing the P214R CoR mutation. Coexpression of each of the CoRs SMRT (silencing mediator for retinoid receptors and TRs) and NCoR (nuclear receptor CoR) enhanced basal stimulation of the negatively regulated promoters in a TR-dependent manner, but this effect was not seen with the P214R TR mutant. The mechanism of CoR effects on negatively regulated promoters was explored further with a series of GAL4-TR chimeric receptors and mutants that allowed TR effects to be assessed independently of receptor interactions with DNA. These experiments revealed that, like the negative regulation of genes by wild-type TR, basal activation occurred with GAL4-TR, but not with the GAL4-P214R mutant, and was reversed by the addition of T3. These results suggest that TR interactions with negatively regulated genes may be driven through protein-protein interactions. We conclude that a subset of negatively regulated genes are controlled by a novel mechanism that involves TR-mediated recruitment and basal activation by SMRT and NCoR. Addition of T3 reverses basal activation, perhaps by dissociation of CoRs.Thyroid hormone receptors (TRs) function as transcription factors to increase or decrease levels of gene expression. In the unliganded state, TRs and retinoic acid receptors can suppress or silence the basal activity of promoters that contain positively regulated hormone response elements (2, 6, 12). The addition of ligand reverses gene silencing and induces strong stimulation of these genes. Recently, nuclear corepressors (CoRs), termed NCoR (nuclear receptor CoR) (22, 25) and SMRT (silencing mediator for retinoid receptors and TRs) (9), were identified and were shown to mediate ligand-independent repression. The CoRs interact with the ligand binding domain (LBD) of nuclear receptors, and several mutations in the CoR box at the amino-terminal end of the LBD have been shown to disrupt interactions with CoRs (9, 22, 25).Although most research in the thyroid hormone action field has involved pathways of positive regulation by triiodothyronine (T3), it has been estimated that nearly equal numbers of genes are repressed in response to T3 in vivo (34). However, the molecular mechanisms responsible for TR-mediated negative regulation remain poorly defined. It i...

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“…The development of clonal cell lines representing the gonadotrope (55) and thyrotrope (2) lineages has greatly facilitated more detailed studies of DNA elements required for tissue-specific expression of the a-subunit gene. Studies using these cell lines have provided information concerning DNA regions important for expression in the pituitary (36,42). This has led to the identification of a gonadotrope-specific DNA element and a factor which interacts with this element (22).…”

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confidence: 99%

Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor.

et al. 1994

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Recently, a pituitary-specific enhancer was identified within the 5' flanking region of The glycoprotein hormones are a family of heterodimeric proteins which consist of a common a subunit noncovalently associated with a hormone-specific 13 subunit (37). The glycoprotein hormones include the pituitary hormones, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone. In addition, some species also synthesize a chorionic gonadotropin within the placenta. Within a species, the glycoprotein hormones all share a common a subunit, while the unique ,B subunits specify the biological activity of the heterodimer. In the pituitary gland, luteinizing hormone and follicle-stimulating hormone are synthesized within cells which are designated gonadotropes, while thyroid-stimulating hormone is synthesized in thyrotropes. Thus, the glycoprotein hormone a-subunit gene is expressed within two different cell types in the pituitary and in some species within the placenta. The mechanisms mediating the tissue-specific expression of the a-subunit gene have been the focus of a large number of studies. While a number of DNA elements which are important for at-subunit expression in the placenta have been identified (3,4,11,12,25,28,34,46), much less is known concerning requirements for expression in the pituitary. It has been demonstrated that reporter genes containing various * Corresponding author. Mailing address:

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Thyrotrope Expression and Thyroid Hormone Inhibition Map to Different Regions of the Mouse Glycoprotein Hormone α-Subunit Gene Promoter*

Cited by 42 publications

References 39 publications

Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein.

Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein.

Nuclear Receptor Corepressors Activate Rather than Suppress Basal Transcription of Genes That Are Negatively Regulated by Thyroid Hormone

Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor.

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