Glucocorticoid Receptor Interaction with 14-3-3 and Raf-1, a Proposed Mechanism for Cross-talk of Two Signal Transduction Pathways

Widén, Christina; Zilliacus, Johanna; Gustafsson, Jan‐Åke; Wikström, Ann–Charlotte

doi:10.1074/jbc.m006943200

Cited by 55 publications

(41 citation statements)

References 28 publications

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“…We speculate that classical GR is involved in TrkB/PLC-␥ signaling because RU486 blocked the inhibitory effect of DEX, and the overexpression and down-regulation of the GR influenced TrkB/PLC-␥ signaling. Raf-1 and 14-3-3 interact with liganded-or nonliganded GR (32), implying that the GR directly influences signaling pathways in cytosol. Moreover, the GR affects the plasma membrane receptor in immune T-cells (30).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter

Numakawa

Kumamaru

Adachi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

184

156

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An increase in glucocorticoid levels and down-regulation of BDNF (brain-derived neurotrophic factor) are supposed to be involved in the pathophysiology of depressive disorders. However, possible crosstalk between glucocorticoid-and BDNF-mediated neuronal functions in the CNS has not been elucidated. Here, we examined whether chronic glucocorticoid exposure influences BDNF-triggered intracellular signaling for glutamate release via a glutamate transporter. We found that chronic exposure to dexamethasone (DEX, a synthetic glucocorticoid) suppressed BDNF-induced glutamate release via weakening the activation of the PLC-␥ (phospholipase C-␥)/Ca 2؉ system in cultured cortical neurons. We demonstrated that the GR (glucocorticoid receptor) interacts with receptor tyrosine kinase for BDNF (TrkB). Following DEX treatment, TrkB-GR interaction was reduced due to the decline in GR expression. Corticosterone, a natural glucocorticoid, also reduced TrkB-GR interaction, BDNF-stimulated PLC-␥, and BDNF-triggered glutamate release. Interestingly, BDNF-dependent binding of PLC-␥ to TrkB was diminished by DEX. SiRNA transfection to induce a decrease in endogenous GR mimicked the inhibitory action of DEX. Conversely, DEX-inhibited BDNF-activated PLC-␥ signaling for glutamate release was recovered by GR overexpression. We propose that TrkB-GR interaction plays a critical role in the BDNF-stimulated PLC-␥ pathway, which is required for glutamate release, and the decrease in TrkB-GR interaction caused by chronic exposure to glucocorticoids results in the suppression of BDNF-mediated neurotransmitter release via a glutamate transporter.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter

Numakawa

Kumamaru

Adachi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

184

156

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“…The cytosolic nonliganded GR is a part of a multiprotein complex in which, among other proteins, two molecules of heat shock protein 90 (hsp90), as well as one molecule each of hsp70 and hsp56 are known to be included. Widen et al 38 identified that Raf-1 copurified with GR with 14-3-3 proteins by immunoaffinity chromatography purification from liver cytosol. Interestingly, hsp90 has been shown to mediate intercellular signal transduction events including B-Raf-mediated activation of mitogen-activated protein kinase cascade by nerve growth factor.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

Kumar¹,

Allen²,

Kieswich³

et al. 2009

Journal of the American Society of Nephrology

109

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In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemiareperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.

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“…57 The corticosteroid receptor and Raf-1, a downstream effector of the signaling factor Ras, are found in a protein complex (the`receptosome'), providing an opportunity for the corticosteroid receptor to crosstalk with the Raf-Ras signaling pathway. 58 These interactions may be involved in regulation of cell proliferation, and induction of cell death by corticosteroids, although experimental evidence to support this concept is presently lacking.…”

Section: Signaling Pathway Crosstalkmentioning

confidence: 99%

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

2002

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Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents. This review examines many facets of the process by which glucocorticoids induce apoptosis. This process is divided into three stages, an initiation stage that involves glucocorticoid receptor-mediated gene regulation, a decision stage that involves the counterbalancing influence of prosurvival and proapoptotic factors, and the execution stage which involves caspase and endonuclease activation. Many aspects of glucocorticoid-induced apoptosis, such as mitochondrial dysfunction and caspase activation, are important steps in virtually all forms of apoptosis. But the process glucocorticoid-induced apoptosis differs from other forms of apoptosis in terms of initiation at the transcriptional level and involvement of the multicatalytic proteasome and calcium. Moreover, the abundant opportunity for crosstalk between the glucocorticoid receptor and other signaling pathways increases the complexity of glucocorticoid-induced apoptosis and its regulation.

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Glucocorticoid Receptor Interaction with 14-3-3 and Raf-1, a Proposed Mechanism for Cross-talk of Two Signal Transduction Pathways

Cited by 55 publications

References 28 publications

Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter

Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

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