Orphan Nuclear Receptor Nur77 Induces Zinc Finger Protein GIOT-1 Gene Expression, and GIOT-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor SF-1 via Recruitment of HDAC2

Song, Kwang Hoon; Park, Yun‐Yong; Kee, Hae Jin; Hong, Chang Yee; Lee, Yong-Soo; Ahn, Seung-Won; Kim, Hye-Jin; Lee, Keesook; Kook, Hyun; Lee, Inkyu; Choi, Hueng‐Sik

doi:10.1074/jbc.m505937200

Cited by 22 publications

(21 citation statements)

References 63 publications

(70 reference statements)

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“…GIOT-4 has been recognized as a member of a Cys 2 -His 2 (C2H2)-type zinc finger protein family, and the protein structure of GIOT-4 is closely related to those of GIOT-1 and GIOT-2 (38, 60). However, its physiological roles in gene regulation have remained to be studied (38,52,60). To examine whether GIOT-4 was a complex component, we then fractionated the ER␤ interactants on a glycerol density gradient (Fig.…”

Section: Resultsmentioning

confidence: 99%

Coactivation of Estrogen Receptor β by Gonadotropin-Induced Cofactor GIOT-4

Kouzu-Fujita

Mezaki

Sawatsubashi

et al. 2009

Molecular and Cellular Biology

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Estrogen exerts its diverse effects through two subtypes of estrogen receptors (ER), ER␣ and ER␤. Each subtype has its own distinct function and expression pattern in its target tissues. Little, however, is known about the transcriptional regulatory mechanism of ER␤ in the major ER␤-expressing tissues. Using biochemical methods, we identified and described a novel ER␤ coactivator. This protein, designated GIOT-4, was biochemically purified from 293F cells. It coactivated ER␤ in ovarian granulosa cells. GIOT-4 expression was induced by stimulation with follicle-stimulating hormone (FSH). GIOT-4 recruited an SWI/SNF-type complex in a ligand-independent manner to ER␤ as an ER subtype-specific physical bridging factor and induced subsequent histone modifications in the ER␤ target gene promoters in a human ovarian granulosa cell line (KGN). Indeed, two ER␤-specific target genes were upregulated by FSH at a specific stage of a normal ovulatory cycle in intact mice. These findings imply the presence of a novel regulatory convergence between the gonadotropin signaling cascade and ER␤-mediated transcription in the ovary.Estrogen plays important roles in many target organs, including the female reproductive organs, the central nervous system, and bone. Estrogen exerts its diverse biological actions through binding to and activating one of two nuclear estrogen receptor (ER) subtypes (ER␣ or ER␤) (12,22,35,40). ERs are members of the nuclear receptor (NR) gene superfamily. ERs, bound to and activated by estrogen, bind to specific DNA sequences called estrogen-responsive elements (ERE) to induce target genes (14,21).Like the other NR members, the ER requires the cooperation of distinct classes of coregulators and multiprotein coregulator complexes in order to initiate estrogen-mediated chromatin reorganization (16,46). These complexes appear to modify the chromatin configuration in a highly regulated manner by controlling nucleosomal rearrangement and enzymecatalyzed modifications of histone tails. By altering chromatin structure, the coregulator complexes facilitate bridging between NRs and basal transcription factors, along with RNA polymerase II, thereby controlling transcription. As for the nucleosomal rearrangement, two major classes of chromatinmodifying complexes that coregulate NRs have been well-characterized. One class is the histone-modifying complexes, including discrete subfamilies of transcription coregulatory complexes (2,29,36). The best-characterized NR coregulator complexes possess either histone acetylase or histone deacetylase activities. Recently, histone methylases/demethylases have also been shown to be significant NR coregulators. The other class of coregulator complexes is ATP-dependent chromatinremodeling complexes. These complexes use ATP hydrolysis to rearrange nucleosomal arrays in a noncovalent manner to facilitate or prevent the access of NRs to nucleosomal DNA (5,17,33). These ATP-dependent chromatin-remodeling complexes have been classified into three subfamilies based on the major catalytic ...

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Section: Resultsmentioning

confidence: 99%

Coactivation of Estrogen Receptor β by Gonadotropin-Induced Cofactor GIOT-4

Kouzu-Fujita

Mezaki

Sawatsubashi

et al. 2009

Molecular and Cellular Biology

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“…Expression of GIOT-1, another repressor found in Leydig cells, is upregulated by NR4A1 in response to LH/cAMP (Song et al 2006). GIOT-1 was shown to act as a repressor of NR5A1-mediated activation of the Cyp17a1 promoter (Song et al 2006). It is therefore possible that the NR0B1 and GIOT-1 repressor, through their interaction with NR4A1 and NR5A1, might also contribute to the Dex-mediated inhibition of cAMP-induced Star expression in Leydig cells.…”

Section: Discussionmentioning

confidence: 99%

“…NR0B1 can also interact with NR4A1 and NR5A1, both activators of Star expression, leading to the repression of their transactivation properties (Ito et al 1997, Song et al 2004, Yu & Li 2006. Expression of GIOT-1, another repressor found in Leydig cells, is upregulated by NR4A1 in response to LH/cAMP (Song et al 2006). GIOT-1 was shown to act as a repressor of NR5A1-mediated activation of the Cyp17a1 promoter (Song et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Martin¹,

Tremblay

2008

Journal of Molecular Endocrinology

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It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at K95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

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“…Effect of water deprivation on the distribution of cells expressing Atf4, Cebpb, Creb3l1, Giot1, and Giot2␤ in the SON and PVN of the control (C) and dehydrated (D been shown to be induced by cAMP intracellular signaling pathways through a CRE (Yazawa et al, 2003). Furthermore, the Giot1 promoter has been shown recently to be a target of the orphan nuclear receptor Nr4a1 (nuclear receptor subfamily 4, group A, member 1) (also known as Nur77 or NGFIB) (Song et al, 2006) transcription factor, which is also upregulated in the SON after dehydration (supplemental Table 3, available at www.jneurosci.org as supplemental material) (Luckman, 1997;Kawasaki et al, 2005). Nr4a1 is also known to be under the control of cAMP pathways (Humphries et al, 2004).…”

Section: Atf4mentioning

confidence: 99%

Transcription Factor Expression in the Hypothalamo-Neurohypophyseal System of the Dehydrated Rat: Upregulation of Gonadotrophin Inducible Transcription Factor 1 mRNA Is Mediated by cAMP-Dependent Protein Kinase A

Qiu¹,

Yao²,

Hindmarch³

et al. 2007

J. Neurosci.

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The supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamo-neurohypophyseal system (HNS) undergo a dramatic function-related plasticity during dehydration. We hypothesize that alterations in steady-state transcript levels might be partially responsible for this remodeling. In turn, regulation of transcript abundance might be mediated by transcription factors. We used microarrays to identify changes in the expression of mRNAs encoding transcription factors in response to water deprivation in the SON. We observed downregulation of 10 and upregulation of 28 transcription factor transcripts. For five of the upregulated mRNAs, namely gonadotropin inducible ovarian transcription factor 1 (Giot1), Giot2, cAMP-responsive element binding protein 3-like 1, CCAAT/enhancer binding protein ␤, and activating transcription factor 4, in situ hybridization was used to confirm the array results, demonstrating a significant increase in expression in SON and PVN magnocellular neurons (MCNs) after 3 d of water deprivation and, in some cases, upregulation in parvocellular PVN neurons. Using a viral vector expressing a potent inhibitor of cAMP-dependent protein kinase A (PKA), we show that the osmotically induced increase in the abundance of transcripts encoding Giot1 is mediated in vivo by the PKA pathway. We thus suggest that signaling pathways activated by dehydration in MCNs mediate transcription factor gene activation, which, in turn, regulate target genes that mediate HNS remodeling.

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Orphan Nuclear Receptor Nur77 Induces Zinc Finger Protein GIOT-1 Gene Expression, and GIOT-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor SF-1 via Recruitment of HDAC2

Cited by 22 publications

References 63 publications

Coactivation of Estrogen Receptor β by Gonadotropin-Induced Cofactor GIOT-4

Coactivation of Estrogen Receptor β by Gonadotropin-Induced Cofactor GIOT-4

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Transcription Factor Expression in the Hypothalamo-Neurohypophyseal System of the Dehydrated Rat: Upregulation of Gonadotrophin Inducible Transcription Factor 1 mRNA Is Mediated by cAMP-Dependent Protein Kinase A

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