Activation and Induction of NUR77/NURR1 in Corticotrophs by CRH/cAMP: Involvement of Calcium, Protein Kinase A, and MAPK Pathways

Kovalovsky, Damián; Refojo, Damián; Liberman, Ana C.; Hochbaum, Daniel; Paez-Pereda, Marcelo; Coso, Omar A.; Stalla, Günter; Holsboer, Florian; Arzt, Eduardo

doi:10.1210/mend.16.7.0863

Cited by 217 publications

(87 citation statements)

References 52 publications

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“…For the NR4A subfamily, the AF1 appears to play the predominant role in transcriptional activation and co-factor recruitment, and its activity can be regulated by phosphorylation (21)(22)(23)(24)(25)(26). Recent results show that the AF1 directly recruits co-activators such as members of the SRC family, p300, pCAF, and DRIP205 (25,26).…”

mentioning

confidence: 99%

Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain

Flaig¹,

Greschik²,

Peluso‐Iltis

et al. 2005

Journal of Biological Chemistry

124

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NGFI-B is a ligand-independent orphan nuclear receptor of the NR4A subfamily that displays important functional differences with its homolog Nurr1. In particular, the NGFI-B ligand-binding domain (LBD) exhibits only modest activity in cell lines in which the Nurr1 LBD strongly activates transcription. To gain insight into the structural basis for the distinct activation potentials, we determined the crystal structure of the NGFI-B LBD at 2.4-Å resolution. Superimposition with the Nurr1 LBD revealed a significant shift of the position of helix 12, potentially caused by conservative amino acids exchanges in helix 3 or helix 12. Replacement of the helix 11-12 region of Nurr1 with that of NGFI-B dramatically reduces the transcriptional activity of the Nurr1 LBD. Similarly, mutation of Met 414 in helix 3 to leucine or of Leu 591 in helix 12 to isoleucine (the corresponding residues found in NGFI-B) significantly affects Nurr1 transactivation. In comparison, swapping the helix 11-12 region of Nurr1 into NGFI-B results in a modest increase of activity. These observations reveal a high sensitivity of LBD activity to changes that influence helix 12 positioning. Furthermore, mutation of hydrophobic surface residues in the helix 11-12 region (outside the canonical co-activator surface constituted by helices 3, 4, and 12) severely affects Nurr1 transactivation. Together, our data suggest that a novel co-regulator surface that includes helix 11 and a specifically positioned helix 12 determine the cell type-dependent activities of the NGFI-B and the Nurr1 LBD.

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mentioning

confidence: 99%

Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain

Flaig¹,

Greschik²,

Peluso‐Iltis

et al. 2005

Journal of Biological Chemistry

124

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“…By 4 h, the relative mRNA levels for Nur77 and [7-12, 20, 21], there has been increased interest in regulation of their expression by various inflammatory stimuli, including LPS [10]. Several studies have shown that NR4A expression can be induced by cAMP [13][14][15][16]19], whose intracellular levels can be increased in response to mediators of inflammation or stress such as prostaglandins or catecholamines. However, potential interactions between LPS and cAMP analogs or cAMP-elevating agents in regulating NR4A expression have not been reported previously.…”

Section: Simultaneous Treatment With 8-bromo-camp Clearly Modified Thmentioning

confidence: 99%

“…The present results indicate that the regulated expression of NR4A members within macrophages in vivo and the resulting functional consequences are likely to be significantly more complex than appreciated from previous studies that evaluated regulation of NR4A expression by single stimuli in cultured cells. In addition to inducing NR4A expression, the cAMP/protein kinase A pathway can enhance transcriptional activity of NR4A receptors independently of changes in NR4A levels [14,22], thus potentially adding yet another layer of regulatory complexity. …”

Section: Simultaneous Treatment With 8-bromo-camp Clearly Modified Thmentioning

confidence: 99%

“…During inflammation or infection in vivo, however, macrophages are exposed to multiple stimuli, which can include agents such as catecholamines or prostaglandins that stimulate intracellular cAMP synthesis, and the responses of specific genes to combinations of stimuli can vary significantly from their responses to individual stimuli. NR4A expression is induced by cAMP in liver, muscle and pituitary cells [13][14][15][16], but it has not been determined previously whether cAMP also induces expression of any of the NR4A isoforms in macrophages or, perhaps more importantly, whether cAMP alters their responses to inflammatory stimuli such as LPS. Therefore, this study was conducted to evaluate the potential impact of cAMP, alone or in combination with LPS, on expression of NR4A family members in macrophage cells.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Induction of NR4A Orphan Nuclear Receptors by LPS and cAMP in Murine Macrophage Cells

Shandilya

Morris

2007

Nature Precedings

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Although NR4A orphan nuclear receptors have been implicated in inflammatory gene expression and atherosclerosis, there is little information regarding their regulation by combinations of stimuli likely to be found in vivo, such as LPS and inducers of cAMP. LPS rapidly induced Nur77 and NOR1 mRNAs but had little effect on expression of Nurr1 mRNA. All three NR4Aswere rapidly induced by 8-bromo-cAMP and remained elevated for at least 8 h. Maximum induction of NOR1 by 8-bromo-cAMP was much greater than with LPS, but maximum induction of Nur77 was similar with both agents. Whereas Nurr1 mRNA had very little response to LPS, it was strongly induced by 8-bromo-cAMP, and Nurr1 mRNA levels remained elevated for at least 20 h. The combination of 8-bromo-cAMP and LPS acted synergistically to strongly induce NOR1 and Nur77, whereas LPS partially inhibited the induction of Nurr1 by 8-bromo-cAMP.Nurr1 protein levels correlated with Nurr1 mRNA levels but exhibited slower response kinetics.In summary, the NR4A receptors did not respond identically to individual stimuli or to combinations of stimuli. In particular, the magnitude of the responses to combinations of stimuli was quite different than to individual stimuli. Thus, NR4A receptor expression and the resulting functional consequences are more complex than appreciated from previous studies that evaluated regulation of NR4A expression by single stimuli. 2Nature Precedings :

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“…At the pituitary level, CRH stimulates the expression of pro-opiomelanocortin (Pomc) and production of adrenocorticotropin (ACTH) (Gagner & turn activate the Pomc promoter. cAMP activates calcium/ calmodulin kinase II and Rap1/B-raf/ERK1/2 (Kovalovsky et al 2002) to induce expression of Nur77/ Nurr1 (Murphy & Conneely 1997, Philips et al 1997, Maira et al 1999, which then triggers transcription of Pomc via the NurRE consensus site in the promoter of Pomc. CRH also induces the transcriptional activity of activating protein 1 (AP1) and CREB, which promotes transcription of Pomc through the AP1-binding site located in the first exon (Boutillier et al 1995(Boutillier et al , 1998.…”

Section: Introductionmentioning

confidence: 99%

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

Labeur¹,

Wölfel²,

Stalla³

et al. 2015

Journal of Molecular Endocrinology

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TMEFF2 is a transmembrane protein with unknown function, containing an altered epidermal growth factor (EGF)-like motif, two follistatin-like domains, and a cytosolic tail with a putative G-protein-activating motif. TMEFF2 is predominantly expressed in brain and prostate and has been implicated in cell signaling, neuronal cell survival, and tumor suppression. We found that expression of TMEFF2 in pituitary corticotrope cells inhibits the effects of corticotropin-releasing hormone (CRH) on the production of intracellular cAMP, and CREB, and transcription of Pomc. Regulation of the activity of CRH by TMEFF2 requires neither the cytoplasmic tail nor the EGF domain, while deletion of the follistatin modules abolishes the inhibitory function of TMEFF2. Moreover, a soluble secreted protein containing the complete extracellular domain is sufficient for inhibition of CRH signaling. TMEFF2-induced inhibition depends on serum components. Furthermore, TMEFF2 regulates the non-canonical activin/BMP4 signaling, PI3K, and Ras/ERK1/2 pathways. Thus, TMEFF2 inhibits the CRH signaling pathway and the PI3K/AKT and Ras/ERK1/2 pathways, contributing to a significant inhibition of transcription of Pomc. We found that expression of TMEFF2 in human Cushing's adenoma is reduced when compared with normal human pituitary, which may indicate that TMEFF2 acts as a tumor suppressor in these adenomas. Furthermore, the overexpression of TMEFF2 decreased proliferation of corticotrope cells. Our results indicate a potential therapeutic use of TMEFF2 or factors that stimulate the activity of TMEFF2 for the treatment of corticotrope tumors in order to reduce their secretion of ACTH and proliferation.

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Activation and Induction of NUR77/NURR1 in Corticotrophs by CRH/cAMP: Involvement of Calcium, Protein Kinase A, and MAPK Pathways

Cited by 217 publications

References 52 publications

Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain

Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain

Synergistic Induction of NR4A Orphan Nuclear Receptors by LPS and cAMP in Murine Macrophage Cells

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

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