UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

Garside, Helen; Waters, C; Berry, Andy; Rice, Lisa; Ardley, Helen C.; White, Anne; Robinson, Philip A.; Ray, David

doi:10.1677/joe.1.06799

Cited by 24 publications

(19 citation statements)

References 27 publications

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“…However, our finding is consistent with the observation that several nuclear receptors including GR are ubiquitinated and degraded in the course of their nuclear activities [21][22][23][24][25][26]. In addition to receptors, studies have revealed that coactivators, including steroid receptor coactivator 1 (SRC1), SRC2, SRC3, CBP and E6-associated protein (E6-AP), could also be ubiquitinated and degraded, through the proteosome, in order to disassemble and reassemble coactivator complexes, thereby promoting enhanced transcription [27].…”

Section: Bag-1m Is Not Involved In the Degradation Of Grsupporting

confidence: 92%

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Wang

Baniahmad

et al. 2009

FEBS Letters

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a b s t r a c tThe Bcl-2 associated athanogene 1M (Bag-1M) is known to repress the transactivation of the glucocorticoid receptor (GR). We report here that Bag-1M inhibits the action of GR via recruitment of corepressors, including nuclear receptor corepressor (NcoR) and silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), and histone deacetylase (HDAC)3 to the genomic response element of a glucocorticoid-regulated human metallothionein IIa (hMTIIa) gene. A mutant GR lacking the interaction with BAG-1M fails to recruit the corepressors NcoR and SMRT. RNAi-mediated knock down of corepressors and the use of HDAC inhibitor relieved Bag-1M-induced repression on the transactivation of the GR. In addition, Bag-1M is not involved in the degradation of the receptor. These findings indicate a novel mechanism by which Bag-1M acts as a corepressor and downregulates the activity of the GR. Structured summary:

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Section: Bag-1m Is Not Involved In the Degradation Of Grsupporting

confidence: 92%

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Wang

Baniahmad

et al. 2009

FEBS Letters

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“…25 Inhibition of GR binding to target gene promoters by antagonists or GR mutation has been shown to abolish transactivation. 35,36 We found that OGD induced significant downregulation of the GR in our cEND in vitro system as did tMCAO in murine brains in vivo. Lack of functional GR prevented transcriptional modulation by GC thereby reversing genomic GC effects such as induction of TJ protein target genes leading to elevation of TER.…”

Section: Kleinschnitz Et Almentioning

confidence: 59%

Glucocorticoid Insensitivity at the Hypoxic Blood–Brain Barrier Can Be Reversed by Inhibition of the Proteasome

Kleinschnitz

Blecharz

Kahles

et al. 2011

Stroke

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Background and Purpose-Glucocorticoids potently stabilize the blood-brain barrier and ameliorate tissue edema in certain neoplastic and inflammatory disorders of the central nervous system, but they are largely ineffective in patients with acute ischemic stroke. The reasons for this discrepancy are unresolved. Methods-To address the molecular basis for the paradox unresponsiveness of the blood-brain barrier during hypoxia, we used murine brain microvascular endothelial cells exposed to O 2 /glucose deprivation as an in vitro model. In an in vivo approach, mice were subjected to transient middle cerebral artery occlusion to induce brain infarctions. Blood-brain barrier damage and edema formation were chosen as surrogate markers of glucocorticoid sensitivity in the presence or absence of proteasome inhibitors. Results-O 2 /glucose deprivation reduced the expression of tight junction proteins and transendothelial resistance in murine brain microvascular endothelial cells in vitro. Dexamethasone treatment failed to reverse these effects during hypoxia. Proteasome-dependent degradation of the glucocorticoid receptor impaired glucocorticoid receptor transactivation thereby preventing physiological glucocorticoid activity. Inhibition of the proteasome, however, fully restored the blood-brain barrier stabilizing properties of glucocorticoid during O 2 /glucose deprivation. Importantly, mice treated with the proteasome inhibitor Bortezomib in combination with steroids several hours after stroke developed significantly less brain edema and functional deficits, whereas respective monotherapies were ineffective. Conclusions-We for the first time show that inhibition of the proteasome can overcome glucocorticoid resistance at the hypoxic blood-brain barrier. Hence, combined treatment strategies may help to combat stroke-induced brain edema formation in the future and prevent secondary clinical deterioration. (Stroke. 2011;42:1081-1089.)Key Words: blood-brain barrier Ⅲ proteasome Ⅲ nuclear receptor Ⅲ steroids Ⅲ stroke D isruption of the blood-brain barrier (BBB) and successive edema formation are pathological hallmarks of various disorders of the central nervous system and can dramatically deteriorate neurological symptoms especially in patients with stroke. Glucocorticoids (GCs) are frequently applied to fight BBB leakage in different central nervous system disorders, but GC efficacy is highly variable. Although GCs diminish edema formation in neuroinflammatory diseases such as acute multiple sclerosis lesions, and in certain brain tumors, this substance class is ineffective or even harmful in acute ischemic stroke. [1][2][3][4][5] This is unfortunate because excessive edema formation is a frequent cause of secondary infarct growth and successive death in patients with stroke. 6 The mechanisms underlying this discrepant GC efficacy are largely unknown and their revelation could help to develop novel antiedematous strategies in many neurological diseases.The biological effects of GC are mediated by the glucocorticoid recepto...

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“…To explore the molecular mechanism underlying potentiation of the GR by CoCl 2 , we measured the expression levels of the GR over time. Measurements were made upon Dex addition since several steroid hormone receptors like ERs or AR are destabilized by ligand binding (Dennis & O'Malley 2005; Garside et al . 2006; Ohtake et al .…”

Section: Resultsmentioning

confidence: 99%

Retracted: A reduction state potentiates the glucocorticoid response through receptor protein stabilization

et al. 2007

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The intracellular redox state regulates all biological processes including gene expression. The glucocorticoid receptor (GR), a hormone-dependent transcription factor, is affected by the redox state. GR translocation from the cytoplasm to the nucleus is regulated by oxidative stress. The molecular mechanism of how the redox state affects GR transcriptional regulation, however, has not been clarified. We identified a deoxidizing agent, cobalt chloride (CoCl 2 ), that potentiates the GR transcriptional effects by stabilizing endogenously expressed GR protein as well as exogenously over-expressed one without affecting GR mRNA level. Consequent GR protein stabilization enhanced co-factor recruitments on the target gene promoters. These results support the existence of a novel redox-dependent mechanism of GR transcriptional regulation mediated by receptor protein stabilization.

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UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

Cited by 24 publications

References 27 publications

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Glucocorticoid Insensitivity at the Hypoxic Blood–Brain Barrier Can Be Reversed by Inhibition of the Proteasome

Retracted: A reduction state potentiates the glucocorticoid response through receptor protein stabilization

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