Short Communication Huwe1 as a therapeutic target for neural injury

Zhou, Jiaojiao; Liu, Q; Mao, Meng; Yu, Tong

doi:10.4238/2014.june.9.18

Cited by 8 publications

(11 citation statements)

References 33 publications

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“…Huwe1 is important for neurogenesis (30); however, the biological function of Huwe1 in neurological diseases remains unknown (36). The present study reported that Huwe1 served a role in the survival of L2.3 cells under the OGD condition, which suggests Huwe1 as a potential target in the treatment of ischemic stroke.…”

Section: Discussionmentioning

confidence: 52%

Huwe1 is a novel mediator of protection of neural progenitor L2.3 cells against oxygen‑glucose deprivation injury

Jiang

et al. 2018

Mol Med Report

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Hypoxic‑ischemic encephalopathy is one of the most notable causes of brain injury in newborns. Cerebral ischemia and reperfusion lead to neuronal damage and neurological disability. In vitro and in vivo analyses have indicated that E3 ubiquitin protein ligase (Huwe1) is important for the process of neurogenesis during brain development; however, the exact biological function and the underlying mechanism of Huwe1 remain controversial. In the present study, neural progenitor cells, L2.3, of which we previously generated from rat E14.5 cortex, were used to investigate the role of Huwe1 and its effects on the downstream N‑Myc‑Delta‑like 3‑Notch1 signaling pathway during oxygen‑glucose deprivation (OGD). To evaluate the role of Huwe1 in L2.3 cells, transduction, cell viability, lactate dehydrogenase, 5‑bromo‑2'deoxyurine incorporation, western blotting and immunocytochemical assays were performed. The results of the present study indicated that Huwe1 rescued L2.3 cells from OGD‑induced insults by inhibiting proliferation and inducing neuronal differentiation. In addition, Huwe1 was suggested to mediate the survival of L2.3 cells by inhibiting the activation of the N‑Myc‑Notch1 signaling pathway. Of note, the effects of Huwe1 on Notch1 signaling were completely abolished by knockdown of N‑Myc, indicating that Huwe1 may require N‑Myc to suppress the activation of the Notch1 signaling in L2.3 cells. The determination of the neuroprotective function of the Huwe1‑N‑Myc‑Notch1 axis may provide insight into novel potential therapeutic targets for the treatment of ischemic stroke.

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Section: Discussionmentioning

confidence: 52%

Huwe1 is a novel mediator of protection of neural progenitor L2.3 cells against oxygen‑glucose deprivation injury

Jiang

et al. 2018

Mol Med Report

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“…In addition to MBP expression that was elevated in the DRα1-mMOG-35-55-treated group, we observed increased expression of genes such as HUWE1, PROSAPOSIN, and MYOCILIN. The ubiquitin ligase HUWE1 was shown to regulate glia differentiation and to have an essential role in the proliferation and differentiation of neural progenitor cells [ 35 , 39 ]. PROSAPOSIN is the precursor protein for four lysosomal activator proteins (saposins A–D), and it can also be secreted as a full-length protein.…”

Section: Discussionmentioning

confidence: 99%

HLA-DRα1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection

Benedek

Meza-Romero

Jordan

et al. 2015

J Neuroinflammation

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BackgroundDRα1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two-domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2β1-containing construct.MethodsIn order to determine whether DRα1-mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRα1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRα1-mMOG-35-55.ResultsWe here demonstrate that DRα1-mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRα1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1β and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1).ConclusionThese findings indicate that the DRα1-mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0342-4) contains supplementary material, which is available to authorized users.

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“…Previous studies showed that the UPS plays a complex and unambiguous role in the pathophysiology of cerebral ischemia-reperfusion injury [ 11 ]. While the 26S proteasome activity recovers in many regions after reperfusion (frontal cortex), in general the proteasome is irreversibly inhibited [ 14 ]. A time-dependent decrease in proteasome activity has also been detected in ipsilateral cortex during 1–24 h reperfusion after transient focal ischemia [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have showed that the major control and selectivity are determined by ubiquitin E3 ligase at the substrate ubiquitination step [ 13 ]. The HECT-domain E3 ligase Huwe1 (HECT, UBA and WWE domain containing 1) is involved in the ubiquitination, degradation of multiple proteins, playing diverse biological roles and the altered expression is detected in multiple diseases [ 14 – 17 ]. Huwe1 is important for neurogenesis in cerebral cortex and possibly brain cancer, thus plays critical roles in nervous system plasticity, regeneration and disease [ 14 ].…”

Section: Backgroundsmentioning

confidence: 99%

“…The HECT-domain E3 ligase Huwe1 (HECT, UBA and WWE domain containing 1) is involved in the ubiquitination, degradation of multiple proteins, playing diverse biological roles and the altered expression is detected in multiple diseases [ 14 – 17 ]. Huwe1 is important for neurogenesis in cerebral cortex and possibly brain cancer, thus plays critical roles in nervous system plasticity, regeneration and disease [ 14 ]. Previous studies have indicated that Gadd45 is ubiquitinated and regulated by proteolysis [ 18 , 19 ].…”

Section: Backgroundsmentioning

confidence: 99%

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Huwe1 interacts with Gadd45b under oxygen-glucose deprivation and reperfusion injury in primary Rat cortical neuronal cells

et al. 2015

Mol Brain

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BackgroundGrowth arrest and DNA-damage inducible protein 45 beta (Gadd45b) is serving as a neuronal activity sensor. Brain ischemia induces the expression of Gadd45b, which stimulates recovery after stroke and may play a protective role in cerebral ischemia. However, little is known of the molecular mechanisms of how Gadd45b expression regulated and the down-stream targets in brain ischemia. Here, using an oxygen-glucose deprivation and reperfusion (OGD/R) model, we identified Huwe1/Mule/ARF-BP1, a HECT domain containing ubiquitin ligase, involved in the control of Gadd45b protein level. In this study, we also investigated the role of Huwe1-Gadd45b mediated pathway in BDNF methylation.ResultsWe found that the depletion of Huwe1 by lentivirus shRNA mediated interference significantly increased the expression of Gadd45b and BDNF at 24 h after OGD. Moreover, treatment with Cycloheximide (CHX) inhibited endogenous expression of Gadd45b, and promoted expression of Gadd45b after co-treated with lentivirus shRNA-Huwe1. Inhibition of Gadd45b by lentivirus shRNA decreased the expression levels of brain derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein (p-CREB) pathway, while inhibition of Huwe1 increased the expression levels of BDNF and p-CREB. Moreover, shRNA-Huwe1 treatment decreased the methylation level of the fifth CpG islands (123 bp apart from BDNF IXa), while shRNA-Gadd45b treatment increased the methylation level of the forth CpG islands (105 bp apart from BDNF IXa).ConclusionsThese findings suggested that Huwe1 involved in the regulation of Gadd45b expression under OGD/R, providing a novel route for neurons following cerebral ischemia-reperfusion injury. It also indicated that the methylation of BDNF IXa was affected by Gadd45b as well as Huwe1 in the OGD/R model.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0178-y) contains supplementary material, which is available to authorized users.

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Short Communication Huwe1 as a therapeutic target for neural injury

Cited by 8 publications

References 33 publications

Huwe1 is a novel mediator of protection of neural progenitor L2.3 cells against oxygen‑glucose deprivation injury

Huwe1 is a novel mediator of protection of neural progenitor L2.3 cells against oxygen‑glucose deprivation injury

HLA-DRα1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection

Huwe1 interacts with Gadd45b under oxygen-glucose deprivation and reperfusion injury in primary Rat cortical neuronal cells

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