FMS-like tyrosine kinase 3 interacts with the glucocorticoid receptor complex and affects glucocorticoid dependent signaling

Asadi, Abolfazl; Hedman, Erik; Widén, Christina; Zilliacus, Johanna; Gustafsson, Jan Åke; Wikström, Ann Charlotte

doi:10.1016/j.bbrc.2008.01.146

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…A study reported direct interaction between FLT3 and dexamethasone to drive glucocorticoid signaling pathway. 45 We hypothesize that mutant and constitutively active FLT3 changes glucocorticoid signaling-mediated apoptosis in cytarabine-resistant AML cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

et al. 2016

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We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.

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Section: Discussionmentioning

confidence: 99%

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

et al. 2016

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“…DDIT4 is a repressor of MTOR ( Gordon et al, 2015 ) and is transcriptionally up-regulated by GC in response to stress and fasting ( Polman et al, 2012 ; McGhee et al, 2009 ). FLT3 is a tyrosine kinase that binds to GR and potentiates its signaling ( Asadi et al, 2008 ). FLT3 also regulates dendritic cell development by activating mTOR signaling ( Chen et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Blood transcriptome based biomarkers for human circadian phase

Laing

Möller-Levet

Poh

et al. 2017

eLife

125

150

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Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.DOI: http://dx.doi.org/10.7554/eLife.20214.001

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“…A similar mechanism might be involved in TrkB-GR interaction. Interestingly, FMS-like tyrosine kinase 3 (Flt3), another member of the receptor tyrosine kinase (RTK) family, interacts with the GR in hematopoietic cells (33). Flt3 interacts with the N-terminal region of the GR in the presence and absence of glucocorticoid.…”

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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FMS-like tyrosine kinase 3 interacts with the glucocorticoid receptor complex and affects glucocorticoid dependent signaling

Cited by 10 publications

References 22 publications

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

Blood transcriptome based biomarkers for human circadian phase

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

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