A role for NRAGE in NF-κB activation through the non-canonical BMP pathway

Matluk, Nicholas; Rochira, Jennifer A.; Karaczyn, Aldona; Adams, Tamara; Verdi, Joseph M.

doi:10.1186/1741-7007-8-7

Cited by 31 publications

(24 citation statements)

References 43 publications

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“…In the heart, unlike our findings in the brain, inhibition of TAK1 by 5Z-7-oxozeaenol led to increased cardiomyocyte death after cardiac ischemia (Sicard, et al, 2009), suggesting that TAK1 has anti-apoptotic effects. In contrast, several studies have shown that activation of TAK1 has enhanced apoptosis via activation of p38 mitogen-activated protein kinase (p38 MAPK) and JNK in fibroblasts (Matluk, et al, 2010, Resch, et al, 2009, Sorrentino, et al, 2008) and both JNK and its downstream target c-Jun, are well recognized pro-apoptotic factors in ischemic brain (Neubert, et al, 2011, Nijboer, et al, 2010) consistent with our results demonstrating neuroprotection and the significant decrease in stroke-induced pJNK levels with TAK inhibition. Therefore, the effects of TAK1 on apoptosis may be dependent on the duration of ischemia, reperfusion status, and the tissue examined, similar to what has been seen with AMPK activation (Weisova, et al, 2011).…”

Section: Discussionsupporting

confidence: 91%

Protection from cerebral ischemia by inhibition of TGFβ-activated kinase

White

Tarabishy

Venna

et al. 2012

Experimental Neurology

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Objective Transforming growth factor-β-activated kinase (TAK1) is a member of the mitogen-activated protein kinase family that plays important roles in apoptosis and inflammatory signaling, both of which are critical components of stroke pathology. TAK1 has recently been identified as a major upstream kinase that phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK), a major mediator of neuronal injury after experimental cerebral ischemia. We studied the functional role of TAK1 and its mechanistic link with AMPK after stroke. Methods Male mice were subjected to transient middle cerebral artery occlusion (MCAO). The TAK1 inhibitor 5Z-7-oxozeaenol was injected either intracerebroventricularly or intraperitoneally at various doses and infarct size and functional outcome after long term survival was assessed. Mice with deletion of the AMPK α2 isoform were utilized to assess the contribution of downstream AMPK signaling to stroke outcomes. Levels of pTAK1, pAMPK, and other TAK1 targets including the pro-apoptotic molecule c-Jun-N-terminal kinase (JNK)/c-Jun and the pro-inflammatory protein cyclooxygenase-2 were also examined. Results TAK1 is critical in stroke pathology. Delayed treatment with a TAK1 inhibitor reduced infarct size and improved behavioral outcome even when given several hours after stroke onset. This protective effect may be independent of AMPK activation but was associated with a reduction in JNK and c-Jun signaling. Conclusions Enhanced TAK1 signaling, via activation of JNK, contributes to cell death in ischemic stroke. TAK1 inhibition is a novel therapeutic approach for stroke as it is neuroprotective with systemic administration, has a delayed therapeutic window, and demonstrates sustained neuroprotective effects.

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Section: Discussionsupporting

confidence: 91%

Protection from cerebral ischemia by inhibition of TGFβ-activated kinase

White

Tarabishy

Venna

et al. 2012

Experimental Neurology

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“…31,32,33 ZFP91 is involved in the activation of NFKB2, 34 while MAGED1 and TRIM4 have both been shown to activate NFKB. 35,36 Knocking down DDX41 inhibits activation of NFKB 37 ( Table 1 and Figure 4 ). These data suggest that miR-140 inhibits the NFKB pathway at several different points of attack.…”

Section: Discussionmentioning

confidence: 97%

microRNA-140 Inhibits Inflammation and Stimulates Chondrogenesis in a Model of Interleukin 1β-induced Osteoarthritis

Karlsen

Souza

Ødegaard

et al. 2016

Molecular Therapy - Nucleic Acids

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Osteoarthritis is a serious disease of articular cartilage. The pathogenic factors contributing to this disorder are inflammation, extracellular matrix degradation and failure to rebuild the articular cartilage. Preclinical studies suggest that microRNA-140 may play a protective role in osteoarthritis development, but little is known about the mechanism by which this occurs. Here we present the results of forced expression of microRNA-140 in an in vitro model of osteoarthritis, evaluated by global proteomics analysis. We show that inflammation was reduced through the altered levels of multiple proteins involved in the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 pathway. microRNA-140 upregulated many of the components involved in the synthesis of hyaline extracellular matrix and reduced the levels of aggrecanases and syndecan 4, thus potentially both increasing cartilage repair and reducing cartilage breakdown. These results show how forced expression of microRNA-140 is likely to counteract all three pathogenic processes, and support the idea that intra-articular injection of microRNA-140 may benefit patients suffering from early osteoarthritis.

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“…Because our transgenes are not under normal regulation, this would not be possible at the level of transcription in this model. Next, BMPR2 has been shown to regulate NF-B through a mechanism involving TAB1/TAK1 and the type 1 BMP receptor [45]; we explicitly chose to use a BMPR2 mutation which left this signaling intact, since both in mice and in humans mutations affecting this pathway are not required for the development of PH. These technical limitations do not alter our primary conclusions, but do limit their scope.…”

Section: Discussionmentioning

confidence: 99%

NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension

et al. 2014

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Abstract:Aim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2 R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling. OPEN ACCESSDiseases 2014, 2 149 Conclusion: NF-κB activation exacerbates, but is not required for Bmpr2-related PH. Pulmonary vascular-specific activation of NF-κB may be a "second hit" that drives penetrance in heritable PH.

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A role for NRAGE in NF-κB activation through the non-canonical BMP pathway

Cited by 31 publications

References 43 publications

Protection from cerebral ischemia by inhibition of TGFβ-activated kinase

Protection from cerebral ischemia by inhibition of TGFβ-activated kinase

microRNA-140 Inhibits Inflammation and Stimulates Chondrogenesis in a Model of Interleukin 1β-induced Osteoarthritis

NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension

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