Nuclear Clusterin Is Associated with Neuronal Apoptosis in the Developing Rat Brain upon Ethanol Exposure

Kim, Nayoung; Han, Jae Yoon; Roh, Gu Seob; Kim, Hee Jin; Kang, Sang Soo; Cho, Gyeong J.; Park, Jae Yong; Choi, Wan Sung

doi:10.1111/j.1530-0277.2011.01588.x

Cited by 16 publications

(23 citation statements)

References 47 publications

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“…To the best of our knowledge, they have distinct biological functions, e.g. sCLU reportedly can prevent cell death while nuclear can promote cell death (Kim et al 2012;Koltai 2014). To clarify the function of sCLU, we utilized intraventricular infusion of exogenous human ApoJ protein following CCI in mice.…”

Section: Discussionmentioning

confidence: 99%

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

Huang

Cheng

Jiang

et al. 2016

Journal of Neurochemistry

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Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in youth, but to date, effective therapies are still lacking. Previous studies revealed a marked response of apolipoprotein J (ApoJ) expression to the brain injury. The aim of this study was to determine the potential roles of ApoJ in functional recovery following TBI. After controlled cortex impact (CCI), a TBI model, in adult wild-type mice, ApoJ expression was up-regulated since 6 h post-injury and sustained for 5 days. Animals infused with recombinant human ApoJ intraventricularly at 30 min prior to CCI showed significantly reduced oxidative stress (3-nitrotyrosine, 4-hydroxynonenal) and complement activation (C5b-9). In addition, ApoJ treatment was shown to suppress the inflammatory response (glial activation, cytokine expression), blood-brain barrier disruption (Evans blue extravasation), and cerebral edema (water content) induced by CCI. Concomitantly, improved neuronal maintenance and neurological behavioral performance were observed in ApoJtreated mice compared with the vehicle group. These findings support a neuroprotective role of ApoJ via multifunctional pathways, providing a novel and encouraging treatment strategy for TBI.

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Section: Discussionmentioning

confidence: 99%

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

Huang

Cheng

Jiang

et al. 2016

Journal of Neurochemistry

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“…We previously proposed that nCLU sequesters the anti-apoptotic Bcl-1 family member, Bcl-xL, via its putative BH3 motif and releases bound Bax, thereby promoting apoptosis accompanied by activation of caspase-3 and release of cytochrome c (Kim and Choi, 2011; Kim et al, 2011; 2012; Lee et al, 2011). These results suggest a novel, nCLU-mediated apoptosis mechanism in normal cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter

Park

Shin³

et al. 2014

Molecules and Cells

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Differential transcription of the clusterin (CLU) gene yields two CLU isoforms, a nuclear form (nCLU) and a secretory form (sCLU), which play crucial roles in prostate tumorigenesis. Pro-apoptotic nCLU and anti-apoptotic sCLU have opposite effects and are differentially expressed in normal and cancer cells; however, their regulatory mechanisms at the transcriptional level are not yet known. Here, we examined the transcriptional regulation of nCLU in response to hypoxia. We identified three putative hypoxia response elements (HREs) in the human CLU promoter between positions −806 and +51 bp. Using a luciferase reporter, electrophoretic gel mobility shift, and chromatin immunoprecipitation assays, we further showed that hypoxia-inducible factor-1α (HIF-1α) bound directly to these sites and activated transcription. Exposure to the hypoxiamimetic compound CoCl2, incubation under 1% O2 conditions, or overexpression of HIF-1α enhanced nCLU expression and induced apoptosis in human prostate cancer PC3M cells. However, LNCaP prostate cancer cells were resistant to hypoxia-induced cell death. Methylation-specific PCR analysis revealed that the CLU promoter in PC3M cells was not methylated; in contrast, the CLU promoter in LNCap cells was methylated. Co-treatment of LNCaP cells with CoCl2 and a demethylating agent promoted apoptotic cell death through the induction of nCLU. We conclude that nCLU expression is regulated by direct binding of HIF-1α to HRE sites and is epigenetically controlled by methylation of its promoter region.

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“…Experimental studies have shown that the mode of death in these neurons is apoptosis [15]. We examined Apo J protein expression in the pons and hippocampus of early liveborn neonatal deaths comparing 12 cases with PSN to 15 controls lacking PSN on histology.…”

Section: Introductionmentioning

confidence: 99%

Retrospective Case-Control Study of Apolipoprotein J/Clusterin Protein Expression in Early Liveborn Neonatal Deaths with and without Pontosubicular Necrosis

Kurian

McGuone

2012

Pathology Research International

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Aims. Our objective was to examine Apo J protein expression in a total of 27 early liveborn neonatal deaths (less than 7 days of age) selected from the Scottish Perinatal Study (gestation of 25–42 weeks) comparing a group with histological pontosubicular necrosis (PSN) (n = 12) to a control group lacking PSN (n = 15). Methods. Using immunohistochemistry we evaluated postmortem pons and hippocampus from patients with PSN versus controls. Results. In the group with PSN, 11/12 (92%) cases showed positive Apo J neurones in the hippocampus/pons compared with 6/15 (40%) cases without PSN (P = 0.014, odds ratio 27.5, 95% confidence interval 2.881–262.48, using exact logistic regression)—independent of gestation, presence or absence of clinical asphyxia, duration of labour, or postnatal age. Clinical asphyxia was present in 10/15 (67%) without PSN compared with 11/12 (92%) with PSN. Neuronal Apo J positivity was present in 15/21 (71%) of clinically asphyxiated cases compared with 2/6 (33%) of the cases with no evidence of clinical asphyxia (P = 0.154, odds ratio 5, 95% confidence interval 0.71 to 34.94). Conclusions. Apo J neuronal protein expression is significantly increased in cases with PSN compared to cases without PSN—independent of gestation, presence of clinical asphyxia, duration of labour, or postnatal age.

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Nuclear Clusterin Is Associated with Neuronal Apoptosis in the Developing Rat Brain upon Ethanol Exposure

Abstract: This study shows that nClu plays a pro-apoptotic role in ethanol-induced cell death in the developing brain, providing new insights for development of FASD.

Cited by 16 publications

References 47 publications

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

Hypoxia Inducible Factor-1α Directly Regulates Nuclear Clusterin Transcription by Interacting with Hypoxia Response Elements in the Clusterin Promoter

Retrospective Case-Control Study of Apolipoprotein J/Clusterin Protein Expression in Early Liveborn Neonatal Deaths with and without Pontosubicular Necrosis

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