Glucocorticoid-Independent Repression of TNF-α-Stimulated IL-6 Expression by the Glucocorticoid Receptor: A Potential Mechanism for Protection Against an Excessive Inflammatory Response

Verhoog, Nicolette; Avenant, Chanel; Kotitschke, Andrea; Hapgood, Janet P.

doi:10.1210/endo-meetings.2011.part3.p16.p3-5

Cited by 9 publications

(11 citation statements)

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“…We found that S226 was not affected by p38 MAPK blockade, suggesting that GR regulation by MAPK is highly cell specific. In addition to the transactivation properties reported in previous studies, Verhoog and colleagues were the first to report ligand-independent transrepression by the GR that was dependent on phosphorylation of unliganded GR at S226 and recruitment of GR interacting protein-1 as a corepressor (42). Whether the transcriptional activation of unliganded GR induced by p38 MAPK blockade showed in the present study requires the recruitment of GRIP-1 remains an interesting possibility.…”

Section: Discussionsupporting

confidence: 67%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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Like many steroid receptors, the glucocorticoid (GC) receptor (GR) is a phosphoprotein. Although there are multiple phosphorylation sites critical for GR transcriptional activity (i.e., serine [S]203, S211, and S226), their respective role in driving GR functions is highly cell specific. We have recently identified protein phosphatase 5 as an essential Ser/Thr phosphatase responsible for impairing GR function via S211 dephosphorylation in airway smooth muscle (ASM) cells. Because p38 mitogen-activated protein kinase (MAPK) directly phosphorylates GR in different cell types in a stimulus-and celldependent manner, we investigated the role of p38 MAPK on GR phosphorylation and function in ASM cells. Cells were transfected with 100 nM p38 MAPK small interfering RNA or 2 mg MAPK kinase 3 expression vector (a specific kinase that directly activates p38 MAPK) in the presence or absence of fluticasone (100 nM) and/or p38 MAPK pharmacological inhibitor SB203580. We found that p38 MAPK blockade positively regulates GR nuclear translocation and GR-dependent induction of the steroid-target gene GC-induced leucine zipper in a hormone-independent manner. We also found that p38 MAPK-dependent regulation of GR functions was associated with a differential action on GR phosphorylation at S203 and S211 residues. This study demonstrated that the inactive state of GR in resting conditions is not only ensured by the absence of the GC ligand but also by p38 MAPK-dependent phosphorylation of unliganded GR at specific residues, which appears to be important in determining the overall GC responsiveness of ASM cells.

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Section: Discussionsupporting

confidence: 67%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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“…The observation of a constitutive positive regulatory role for GR in the absence of ligand is unique and adds a new dimension to the GR pathway. A recent publication has reported negative regulation of the interleukin (IL)-6 gene by GR in the absence of ligand (25), but this effect is dependent on TNF-a and is thus not a constitutive change as we have observed. Indeed, reports of ligand-independent activation by other steroid hormone receptors have typically been in response to other stimuli (49).…”

Section: -Hc +Hcsupporting

confidence: 48%

“…While it has traditionally been accepted that nuclear receptors are activated in response to ligand binding, several reports exist of progesterone and estrogen receptor activation and nuclear activity even in the absence of hormone (21). GR has been reported to be activated by various stimuli in the absence of glucocorticoid ligands (21)(22)(23)(24), and unliganded GR has recently been found to bind directly to and exert a repressive effect on the IL-6 promoter in response to TNF-a in endocervical cells (25). In addition, it has been suggested that breast cancer progression may be associated with an accumulation of GR in the cytoplasm of tumor cells (26).…”

Section: Introductionmentioning

confidence: 99%

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Ritter

Antonova

Mueller

2012

Molecular Cancer Research

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Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the b-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPb interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk. Mol Cancer Res; 10(4); 558-69. Ó2012 AACR. IntroductionGerm line mutations in the BRCA1 tumor suppressor contribute to familial breast tumor formation but BRCA1 mutations do not seem to occur in sporadic breast cancer tumors (1). Instead, sporadic breast tumors exhibit decreased levels of BRCA1 expression, and the degree of downregulation seems to be correlated with tumor grade, rate of tumor progression, and risk of metastasis (2-6). This implies that loss of BRCA1 function, either through decreased activity or downregulation of expression, is a critical event in the etiology of breast cancer. Phenotypically normal breast epithelial cells from individuals harboring a BRCA1 germ line mutation (a so called "one-hit" mutation accompanied by a 50% decrease in BRCA1 function) express an altered mRNA profile compared with normal cells from individuals without a BRCA1 mutation (7). This suggests that decreases in functional BRCA1

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“…Indeed the unliganded GR attenuates TNF-stimulated IL-6 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and GRIP-1 to the IL-6 promoter. It is suggested that such an autoregulatory mechanism may prevent overproduction of IL-6 in the endocervix, possibly protecting against negative effects of excessive inflammation (Verhoog et al, 2011). However GCs are also reported to induce, rather than to inhibit, the secretion of MIF (Calandra et al, 1995), thus counteracting the hormone inhibition of pro-inflammatory cytokine production.…”

Section: Influence Of Gcs On Tlr and Mifmentioning

confidence: 99%

The Role of Glucocorticoids in Pregnancy: Four Decades Experience with Use of Betamethasone in the Prevention of Pregnancy Loss

Vesce¹,

Giugliano²,

Cagnazzo³

et al. 2012

Glucocorticoids - New Recognition of Our Familiar Friend

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Glucocorticoid-Independent Repression of TNF-α-Stimulated IL-6 Expression by the Glucocorticoid Receptor: A Potential Mechanism for Protection Against an Excessive Inflammatory Response

Cited by 9 publications

References 0 publications

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

The Role of Glucocorticoids in Pregnancy: Four Decades Experience with Use of Betamethasone in the Prevention of Pregnancy Loss

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