Coregulatory protein–orphan nuclear receptor interactions in the human adrenal cortex

Kelly, Sinead; McKenna, T. J.; Young, Leonie S.

doi:10.1677/joe.1.06005

Cited by 12 publications

(6 citation statements)

References 48 publications

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“…H295R cells respond to Ang II acutely with changes in gene transcription including the induction of all members of the NGFI-B family of nuclear hormone receptors (Bassett et al 2004c, Kelly et al 2005, Nogueira et al 2007, Romero et al 2004). In the present study, H295R cells were co-transfected with NGFI-B, NURR-1, or NOR-1 plasmids and luciferase reporter-vectors linked to the promoter region of StAR, CYP11A1, CYP21, HSD3B2, or CYP11B2.…”

Section: Resultsmentioning

confidence: 99%

Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis

Nogueira¹,

Xing

Morris

et al. 2009

Journal of Molecular Endocrinology

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Aldosterone is principally synthesized in the zona glomerulosa of the adrenal by a series of enzymatic reactions leading to the conversion of cholesterol to aldosterone. Angiotensin II (Ang II) is the major physiological regulator of aldosterone production acting acutely to stimulate aldosterone biosynthesis and chronically to increase the capacity of the adrenals to produce aldosterone. We previously defined eight transcription factors that are rapidly induced following Ang II treatment using three in vitro adrenocortical cell models. Herein, we investigated the function of these transcription factors in the regulation of the enzymes needed for aldosterone production. H295R adrenal cells were co-transfected with expression vectors for each transcription factor and promoter/reporter constructs prepared for genes encoding the enzymes needed for aldosterone production. NGFI-B family members induced promoter activity of 3-beta-hydroxysteroid-dehydrogenase type 2 (HSD3B2), 21-hydroxylase (CYP21), and aldosterone synthase (CYP11B2). The importance of NGFI-B in the regulation of CYP11B2 was also demonstrated by reduced CYP11B2 transcription in the presence of a dominant-negative (DN)-NGFI-B. A pharmacological approach was used to characterize the Ang II pathways regulating transcription of NGFI-B family genes. Transcription of NGFI-B members were decreased following inhibition of Ang II type 1 receptor (AT1R), protein kinase C (PKC), calcium/calmodulin-dependent kinases (CaMK), and Src tyrosine kinase (SRC). Taken together, these results suggest that Ang II binding to the AT1R increases activity of PKC, CaMK, and SRC, which act to increase expression of the family of NGFI-B genes as well as CYP11B2. Ang II induction of the NGFI-B family members represents an important pathway to increase the capacity of adrenal cells to produce aldosterone.

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Section: Resultsmentioning

confidence: 99%

Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis

Nogueira¹,

Xing

Morris

et al. 2009

Journal of Molecular Endocrinology

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“…Therefore, as shown in Figure 9 as a proposed model of action of TRH on the TSHβ gene, NR4A1 may also be critical and cooperatively work with Pit1 and GATA2 as an up-regulator of TRH-induced stimulation of the TSHβ gene through this region -128 and +8 close to the TSS. Although interactions of NR4A1 with several transcription factors and coregulators, including silencing mediator for retinoid and thyroid hormones (SMRT), steroid receptor coactivator (SRC-1), TRAP220, and SIN3B/KDM5A and Z3 (ZMYND8-containing) complex have been reported, those with Pit1 and GATA2 remain to be studied [52], [65]–[67].…”

Section: Discussionmentioning

confidence: 99%

NR4A1 (Nur77) Mediates Thyrotropin-Releasing Hormone-Induced Stimulation of Transcription of the Thyrotropin β Gene: Analysis of TRH Knockout Mice

et al. 2012

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Thyrotropin-releasing hormone (TRH) is a major stimulator of thyrotropin-stimulating hormone (TSH) synthesis in the anterior pituitary, though precisely how TRH stimulates the TSHβ gene remains unclear. Analysis of TRH-deficient mice differing in thyroid hormone status demonstrated that TRH was critical for the basal activity and responsiveness to thyroid hormone of the TSHβ gene. cDNA microarray and K-means cluster analyses with pituitaries from wild-type mice, TRH-deficient mice and TRH-deficient mice with thyroid hormone replacement revealed that the largest and most consistent decrease in expression in the absence of TRH and on supplementation with thyroid hormone was shown by the TSHβ gene, and the NR4A1 gene belonged to the same cluster as and showed a similar expression profile to the TSHβ gene. Immunohistochemical analysis demonstrated that NR4A1 was expressed not only in ACTH- and FSH- producing cells but also in thyrotrophs and the expression was remarkably reduced in TRH-deficient pituitary. Furthermore, experiments in vitro demonstrated that incubation with TRH in GH4C1 cells increased the endogenous NR4A1 mRNA level by approximately 50-fold within one hour, and this stimulation was inhibited by inhibitors for PKC and ERK1/2. Western blot analysis confirmed that TRH increased NR4A1 expression within 2 h. A series of deletions of the promoter demonstrated that the region between bp -138 and +37 of the TSHβ gene was responsible for the TRH-induced stimulation, and Chip analysis revealed that NR4A1 was recruited to this region. Conversely, knockdown of NR4A1 by siRNA led to a significant reduction in TRH-induced TSHβ promoter activity. Furthermore, TRH stimulated NR4A1 promoter activity through the TRH receptor. These findings demonstrated that 1) TRH is a highly specific regulator of the TSHβ gene, and 2) TRH mediated induction of the TSHβ gene, at least in part by sequential stimulation of the NR4A1-TSHβ genes through a PKC and ERK1/2 pathway.

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“…This is also the mechanism of Nur77 activation by adrenocorticotrophic hormone, involving dephosphorylation at the same residue, although, unlike at the FSHb gene, the phosphorylation prevented DNA binding in the contexts tested (65). Although we have yet to determine the function of this dephosphorylation in FSHb gene activation, Nur77 is known to interact with SMRT, which represses expression of the FSHb gene in these cells (26,66,67). It is therefore quite possible that the dephosphorylation causes a switch in Nur77 interacting proteins, allowing it to dissociate from SMRT and recruit coactivators.…”

Section: Calcineurin Regulates Gonadotrophin Gene Expression Via Nuclmentioning

confidence: 96%

Gonadotrophin‐Releasing Hormone Signalling Downstream of Calmodulin

Melamed

Savulescu

Lim

et al. 2012

J Neuroendocrinology

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Gonadotrophin‐releasing hormone (GnRH) regulates reproduction via binding a G‐protein coupled receptor on the surface of the gonadotroph, through which it transmits signals, mostly via the mitogen‐activated protein (MAPK) cascade, to increase synthesis of the gonadotrophin hormones: luteinising hormone (LH) and follicle‐stimulating hormone (FSH). Activation of the MAPK cascade requires an elevation in cytosolic Ca2+ levels, which is a result of both calcium influx and mobilisation from intracellular stores. However, Ca2+ also transmits signals via an MAPK‐independent pathway, through binding calmodulin (CaM), which is then able to bind a number of proteins to impart diverse downstream effects. Although the ability of GnRH to activate CaM was recognised over 20 years ago, only recently have some of the downstream effects been elucidated. GnRH was shown to activate the CaM‐dependent phosphatase, calcineurin, which targets gonadotrophin gene expression both directly and indirectly via transcription factors such as nuclear factor of activated T‐cells and Nur77, the Transducer of Regulated CREB (TORC) co‐activators and also the prolyl isomerase, Pin1. Gonadotrophin gene expression is also regulated by GnRH‐induced CaM‐dependent kinases (CaMKs); CaMKI is able to derepress the histone deacetylase‐inhibition of β‐subunit gene expression, whereas CaMKII appears to be essential for the GnRH‐activation of all three subunit genes. Asides from activating gonadotrophin gene expression, GnRH also exerts additional effects on gonadotroph function, some of which clearly occur via CaM, including the proliferation of immature gonadotrophs, which is dependent on calcineurin. In this review, we summarise these pathways, and discuss the additional functions that have been proposed for CaM with respect to modifying GnRH‐induced signalling pathways via the regulation of the small GTP‐binding protein, Gem, and/or the regulator of G‐protein signalling protein 2.

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Coregulatory protein–orphan nuclear receptor interactions in the human adrenal cortex

Cited by 12 publications

References 48 publications

Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis

Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis

NR4A1 (Nur77) Mediates Thyrotropin-Releasing Hormone-Induced Stimulation of Transcription of the Thyrotropin β Gene: Analysis of TRH Knockout Mice

Gonadotrophin‐Releasing Hormone Signalling Downstream of Calmodulin

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