NF‐κB‐dependent regulation of brain‐derived neurotrophic factor in hippocampal neurons by X‐linked inhibitor of apoptosis protein

Kairisalo, Minna; Korhonen, Laura; Sepp, Mari; Pruunsild, Priit; Kukkonen, Jyrki P.; Kivinen, Jenny; Timmusk, Tõnis; Blomgren, Klas; Lindholm, Dan

doi:10.1111/j.1460-9568.2009.06898.x

Cited by 59 publications

(49 citation statements)

References 35 publications

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“…Third, BDNF and inflammatory cytokines both influence serotonin transporter transcription and function (Mossner et al, 2000;Mossner et al, 1998;Zhu et al, 2006;Zhu et al, 2010). IFN-a increases serotonin transporter transcription via the MAP kinase intracellular signaling pathway (Tsao et al, 2008), and both BDNF and inflammatory cytokines share overlapping intracellular signal transduction pathways including MAP kinases (Duman et al, 2007;Zhu et al, 2010) and NF-kappaB (Kairisalo et al, 2009). Fourth, the BDNF Met allele has been associated with an elevated cortical response to a dexamethasone/corticosterone releasing hormone challenge (Schule et al, 2006), which is notable given that there is a greater cortical response to the initial injection of IFN-a in those at increased risk for subsequent depression (Raison et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brainderived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-a), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-a treatment (F 144,17.2 ¼ 6.8; Po0.0001). However, although the Met allele was associated with lower BDNF levels (F 1,83.0 ¼ 5.0; P ¼ 0.03), it was only associated with increased MADRS scores (F 4,8.9 ¼ 20.3; Po0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-a therapy further lowered BDNF serum levels (F 4,37.7 ¼ 5.0; P ¼ 0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-a worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR. Neuropsychopharmacology (2013) 38, 985-995;

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Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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“…AP-1 transcription factors, consisting of Fos and Jun family members, are immediate early genes, whose expression in the CNS is induced by various stimuli, including hypoxia, sensory stimulation, neurotransmitters, neurotrophins, and other growth factors (Sheng and Greenberg, 1990;Radler-Pohl et al, 1993;Karin et al, 1997;Herdegen and Leah, 1998). AP-1 proteins have a conserved basic leucine zipper domain, where the leucine zipper mediates protein dimerization and the basic region is responsible for binding to DNA (Eferl and Wagner, 2003).…”

Section: Introductionmentioning

confidence: 99%

AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons

et al. 2016

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Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates both survival and differentiation of several neuronal populations in the nervous system during development, as well as synaptic plasticity in the adult brain. BDNF exerts its biological functions through its receptor TrkB. Although the regulation of BDNF transcription by neuronal activity has been widely studied, little is known about TrkB signaling-dependent expression of BDNF. Using rat primary cortical neuron cultures, we show that the BDNF gene is a subject to an extensive autoregulatory loop, where TrkB signaling upregulates the expression of all major BDNF transcripts, mainly through activating MAPK pathways. Investigating the mechanisms behind this autoregulation, we found that AP-1 transcription factors, comprising Jun and Fos family members, participate in the induction of BDNF exon I, III, and VI transcripts. AP-1 transcription factors directly upregulate the expression of exon I transcripts by binding two novel AP-1 cis-elements in promoter I. Moreover, our results show that the effect of AP-1 proteins on the activity of rat BDNF promoters III and VI is indirect, because AP-1 proteins were not detected to bind the respective promoter regions by chromatin immunoprecipitation (ChIP). Collectively, we describe an extensive positive feedback system in BDNF regulation, adding a new layer to the elaborate control of BDNF gene expression.

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“…The cAMP signaling system phosphorylates and activates the transcription factor, cAMP responsive element-binding protein, and stimulates the transcription of exon IV (15,45,46). Other transcription factors, such as basic HLHB2 and NFB, have also been implicated in the expression of exon IV (47,48). Little attention has been paid to the regulation of exon IX, except for a reported epigenetic regulation by Gadd45b, a neural immediate early gene, which promotes activity-dependent demethylation of the exon IX promoter (49).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Brain-derived Neurotrophic Factor Coding Exon IX

Nair

Wong‐Riley

2016

Journal of Biological Chemistry

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Brain-derived neurotrophic factor (BDNF) is an active neurotrophin abundantly expressed throughout the nervous system. It plays an important role in synaptic transmission, plasticity, neuronal proliferation, differentiation, survival, and death. The Bdnf gene in rodents has eight non-coding exons and only a single coding exon (IX). Despite its recognized regulation by neuronal activity, relatively little is known about its transcriptional regulation, and even less about the transcription factor candidates that may play such a role. The goal of the present study was to probe for such a candidate that may regulate exon IX in the rat Bdnf gene. Our in silico analysis revealed tandem binding sites for nuclear respiratory factor 2 (NRF-2) on the promoter of exon IX. NRF-2 is of special significance because it co-regulates the expressions of mediators of energy metabolism (cytochrome c oxidase) and mediators of neuronal activity (glutamatergic receptors). To test our hypothesis that NRF-2 also regulates the Bdnf gene, we performed electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), promoter cloning, and site-directed mutagenesis, real-time quantitative PCR (RT-qPCR), and Western blotting analysis. Results indicate that NRF-2 functionally regulates exon IX of the rat Bdnf gene. The binding sites of NRF-2 are conserved between rats and mice. Overexpressing NRF-2 up-regulated the expression of Bdnf exon IX, whereas knocking down NRF-2 down-regulated such expression. These findings are consistent with our hypothesis that NRF-2, in addition to regulating the coupling between neuronal activity and energy metabolism, also regulates the expression of BDNF, which is intimately associated with energy-demanding neuronal activity.

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NF‐κB‐dependent regulation of brain‐derived neurotrophic factor in hippocampal neurons by X‐linked inhibitor of apoptosis protein

Cited by 59 publications

References 35 publications

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons

Transcriptional Regulation of Brain-derived Neurotrophic Factor Coding Exon IX

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