cAMP Response Element-binding Protein-binding Protein Mediates Thyrotropin-releasing Hormone Signaling on Thyrotropin Subunit Genes

Hashimoto, Kazuhito; Zanger, Kerstin; Hollenberg, Anthony N.; Cohen, Laurie E.; Radovick, Sally; Wondisford, Fredric E.

doi:10.1074/jbc.m006819200

Cited by 59 publications

(33 citation statements)

References 45 publications

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“…The construction of thyroid hormone-responsive luciferase reporter genes (DRϩ4-TKLuc, LAP-TKLuc, and PAL-TKLuc) has been reported previously (23). Negatively regulated gene promoters in the identical luciferase reporter (pA3Luc) have also been described: human TRH Ϫ900 to ϩ55, human TSH-␣ Ϫ846 to ϩ44, and human TSH-␤ Ϫ1192 to ϩ37 bp (36). The hybrid TR/GRE 3, as two copies, was inserted upstream of TK 109 in pA3Luc.…”

Section: Methodsmentioning

confidence: 99%

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa

Hollenberg

Wondisford

2003

Journal of Biological Chemistry

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117

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The ␤ isoform of thyroid hormone receptor (TR-␤) has a key role in the feedback regulation of the hypothalamic-pituitary-thyroid (H-P-T) axis. The mechanism of trans-repression of the hypothalamic thyrotropin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH) subunit genes, however, remains poorly understood. A number of distinct mechanisms for TR-␤-mediated negative regulation by thyroid hormone have been proposed, including those that require and do not require DNA binding. To clarify the importance of DNA binding in negative regulation, we constructed a DNA-binding mutant of TR-␤ in which two amino acids within the P box were altered (GSG for EGG) to resemble that found in the glucocorticoid receptor (GR). We termed this mutant GS125, and as expected, it displayed low binding affinities for positive and negative thyroid hormone-response element (pTRE and nTRE, respectively) in gel-mobility shift assays. In transient transfection assays, the GS125 mutant abolished transactivation on three classic pTREs (DR؉4, LAP, and PAL) and all negatively regulated promoters in the H-P-T axis (TRH, TSH-␤, and TSH-␣). However, GS125 TR-␤ bound to a composite TR/GR-response element and was fully functional on this hybrid TR/GR-response element. Moreover, the GS125 TR-␤ mutant displayed normal interactions with transcriptional cofactors in mammalian twohybrid assays. These data do not support a DNA-binding independent mechanism for thyroid hormone negative regulation in the H-P-T axis.The synthesis and secretion of thyroid hormones are exquisitely regulated by a negative feedback system that involves the hypothalamus, pituitary, and thyroid gland (the hypothalamicpituitary-thyroid axis: H-P-T axis). 1 The synthesis of thyrotropin-releasing hormone (TRH), produced in the paraventricular nucleus of the hypothalamus, and the ␣ and ␤ subunits of thyrotropin (thyroid-stimulating hormone; TSH) in the anterior lobe of the pituitary is inhibited at the transcriptional level by thyroid hormone (T 3 ) (1-4). Negative regulation of gene expression by T 3 is an integral part of the function in the H-P-T axis, and these effects are mediated by the ␤ isoform of the thyroid hormone receptors (TR-␤). Of the ␤ isoforms, TR-␤2 is quantitatively and functionally more important than TR-␤1 in regulating the hypothalamus and pituitary (5-8). The molecular mechanisms responsible for TR-mediated negative regulation of target genes are not well understood.In the traditional model of TR action, TR regulates gene expression by binding to specific thyroid hormone-response elements (TRE) on target genes. A number of artificial and natural positive thyroid hormone-response elements (pTREs) have been described, and they can be classified based on the half-site arrangement in the element: DRϩ4, PAL, and LAP (LYS) (9 -11). On target genes negatively regulated by T 3 , response elements (nTREs) have been described in the TRH and TSH-␤ subunit genes (12-17). In these nTREs, TR bound as a monomer to widely spaced half-sites or in the case of...

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Section: Methodsmentioning

confidence: 99%

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Shibusawa

Hollenberg

Wondisford

2003

Journal of Biological Chemistry

Self Cite

117

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“…Expression of TSH␤ is positively regulated by hypothalamic TRH and inhibited by TH feedback regulation. Recent studies have shown that CBP and Pit1 act synergistically in TRH stimulation of the TSH␤ promoter via Pit1 binding sites (105), and phosphorylation of CBP by PKC is critical for Pit1-dependent gene activation (323). TH-dependent negative regulation of TSH␤ transcription is mediated by the ␤-isoform of TR (TR-␤) through an element downstream from the transcription start site via recruiting HDAC activity (1,82,244).…”

Section: H Regulation Of Tsh␤ Gene Expressionmentioning

confidence: 99%

Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

Zhu

Gleiberman²,

Rosenfeld³

2007

Physiological Reviews

320

296

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The pituitary gland is a central endocrine organ regulating basic physiological functions, including growth, the stress response, reproduction, metabolic homeostasis, and lactation. Distinct hormone-producing cell types in the anterior pituitary arise from a common ectodermal primordium during development by extrinsic and intrinsic mechanisms, providing a powerful model system for elucidating general principles in mammalian organogenesis. The central purpose of this review is to inspect the integrated signaling and transcriptional events that affect precursor proliferation, cell lineage commitment, terminal differentiation, and physiological regulation by hypothalamic tropic factors.

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“…For instance, recruitment of CREB binding protein (CBP) by Pit-1 is required for PKA activation of the PRL promoter. Competition between the corepressor N-CoR and the coactivator CBP modulates the transcriptional activity of Pit-1 (Xu et al 1998, Hashimoto et al 2000, Scully et al 2000, Zanger et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Repression of the prolactin promoter: a functional consequence of the heterodimerization between Pit-1 and Pit-1 β

Sporici

Hodskins²,

Locasto³

et al. 2005

Journal of Molecular Endocrinology

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The POU-homeodomain transcription factor Pit-1 is required for the differentiation of the anterior pituitary cells and the expression of their hormone products. Pit-1 , an alternate splicing isoform, has diametrically different outcomes when it is expressed in different cell types. Pit-1 acts as a transcriptional repressor of prolactin (PRL) and growth hormone genes in pituitary cells, and as a transcriptional activator in non-pituitary cells. In order to explore these differences, we: (1) identified the transcriptional cofactors necessary for reconstitution of repression in non-pituitary cells; (2) tested the effect of the -domain on heterodimerization with Pit-1 and physical interaction with the co-activator CREB binding protein (CBP); and (3) determined the -domain sidechain chemistry requirements for repression. Co-expression of both Pit-1 isoforms reconstituted the repression of the PRL promoter in non-pituitary cells. The -domain allowed heterodimerization with Pit-1 but blocked physical interaction with CBP, and specific chemical properties of the -domain beyond hydrophobicity were dispensable. These data strongly suggest that Pit-1 represses hormone gene expression by heterodimerizing with Pit-1 and interfering with the assembly of the Pit-1-CBP complex required for PRL promoter activity in pituitary cells.

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cAMP Response Element-binding Protein-binding Protein Mediates Thyrotropin-releasing Hormone Signaling on Thyrotropin Subunit Genes

Cited by 59 publications

References 45 publications

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

Repression of the prolactin promoter: a functional consequence of the heterodimerization between Pit-1 and Pit-1 β

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