Transcription of the Human Thyrotropin-Releasing Hormone Receptor Gene—Analysis of Basal Promoter Elements and Glucocorticoid Response Elements

Høvring, Per Ivar; Matre, Vilborg; Fjeldheim, Åse-Karine; Løseth, Ole-Petter; Gautvik, Kaare M.

doi:10.1006/bbrc.1999.0545

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…On the other hand, sequences in the first intron of hsp90␣ mediate inhibition of hsp90␣ expression (Zhang et al 1999). There are also examples of regulatory elements in introns that alone are inactive but are necessary for maximum activation of gene expression through HREs in the promoter (Hovring et al 1999;Jackson-Hayes et al 2003). As described above, the majority of intronic regulatory elements are found in the first intron (intron A).…”

Section: Discussionmentioning

confidence: 99%

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

Hubler¹,

Scammell²

2004

Cell Stress Chaper

172

132

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Expression of FKBP51, a large molecular weight immunophilin, is strongly enhanced by glucocorticoids, progestins, and androgens. However, the activity of a 3.4-kb fragment of the FKBP51 gene (FKBP5) promoter was only weakly increased by progestin and we show here that it is unresponsive to glucocorticoids and androgens. The entire FKBP5 was scanned for consensus hormone response elements (HREs) using MatInspector. We found that 2 regions of intron E, which are conserved in rat and mouse FKBP5, contain HRE-like sequences with high match scores. Deoxyribonucleic acid fragments (approximately 1 kb in length) containing these regions were amplified and tested in reporter gene assays for steroid responsiveness. One region of intron E of FKBP5 (pIE2) conferred both glucocorticoid and progestin responsiveness to 2 heterologous reporter genes, whereas the other, less-conserved region of intron E (pIE1) was responsive only to progestins. The inclusion of pIE1 upstream of pIE2 (pIE1IE2) enhanced progestin but not glucocorticoid responsiveness. None of the constructs containing intronic sequences was responsive to androgens. Mutation of the putative HREs within pIE1 and pIE2 eliminated hormone responsiveness. Electrophoretic mobility shift assays demonstrated that progesterone receptors (PR) bound to the HRE in pIE1, whereas both PR and glucocorticoid receptors interacted with the HRE in pIE2. These data suggest that distal intronic elements significantly contribute to transcriptional regulation of FKBP5 by glucocorticoids and progestins.

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Section: Discussionmentioning

confidence: 99%

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

Hubler¹,

Scammell²

2004

Cell Stress Chaper

172

132

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“…To further study the pituitary cell-autonomous regulation of TRHR expression, we employed a rat pituitary cell line (GH4C1), which has been previously used to study TRHR expression (33). Although incubation with either a PI3K or an ERK inhibitor did not have an effect on TRHR expression, incubation with a JNK inhibitor significantly increased TRHR expression by 70% (Fig.…”

Section: Jnk1mentioning

confidence: 99%

Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism

Belgardt

Mauer

Wunderlich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

183

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c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance. Here we demonstrate that JNK activation not only occurs in peripheral tissues, but also in the hypothalamus and pituitary of obese mice. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry, we have generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1 ΔNES mice). JNK1 ΔNES mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues, improved glucose metabolism, as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Moreover, JNK1 ΔNES mice also show reduced somatic growth in the presence of reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations, as well as increased thyroid axis activity. Collectively, these experiments reveal an unexpected, critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis.brain | diabetes | obesity | inflammation | insulin resistance

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“…The strongest of these sites, Pit-1B, is located only 40 bp downstream of the strong TR10 MRE. We have previously also reported the identification of a response element for the glucocorticoid receptor in intron 1 (proximal GRE) [18]. Other predicted candidate sites are present, but remain to be investigated.…”

Section: Discussionmentioning

confidence: 93%

“…These Pit-1 sites are likely to be important determinants for the cell-type-specific expression of the receptor gene in the anterior pituitary. In addition, two glucocorticoid response elements were identified and found to be necessary for transcriptional regulation of the TRHR gene by glucocorticoids [18]. The analysis of the TRHR promoter also revealed several potential binding sites for transcription factors that normally exert their functions during proliferation and differentiation of haematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb

Matre

Høvring

Fjeldheim

et al. 2003

Biochemical Journal

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Thyrotropin-releasing hormone (TRH) receptor (TRHR) is a G-protein-coupled receptor playing a crucial role in the anterior pituitary where it controls the synthesis and secretion of thyroidstimulating hormone and prolactin. Its widespread presence not only in the central nervous system, but also in peripheral tissues, including thymus, indicates other important, but unknown, functions. One hypothesis is that the neuropeptide TRH could play a role in the immune system. We report here that the human TRHR promoter contains 11 putative response elements for the haematopoietic transcription factor c-Myb and is highly Mybresponsive in transfection assays. Analysis of Myb binding to putative response elements revealed one preferred binding site in intron 1 of the receptor gene. Transfection studies of promoter deletions confirmed that this high-affinity element is necessary for efficient Myb-dependent transactivation of reporter plasmids in CV-1 cells. The Myb-dependent activation of the TRHR promoter was strongly suppressed by expression of a dominant negative Myb-Engrailed fusion. In line with these observations, reverse transcriptase PCR analysis of rat tissues showed that the TRHR gene is expressed both in thymocytes and bone marrow. Furthermore, specific, high-affinity TRH agonist binding to cell-surface receptors was demonstrated in thymocytes and a haematopoietic cell line. Our findings imply a novel functional link between the neuroendocrine and the immune systems at the level of promoter regulation.

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Transcription of the Human Thyrotropin-Releasing Hormone Receptor Gene—Analysis of Basal Promoter Elements and Glucocorticoid Response Elements

Cited by 15 publications

References 47 publications

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids

Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism

The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb

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