Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons

Hung Li Wang, Cai Ying He, An Hsun Chou, Tu Hsueh Yeh, Ying Ling Chen, Allen Hon Lun Li

研究成果: 雜誌貢獻文章

15 引文 (Scopus)

摘要

Our recent study indicated that polyglutamine-expanded ataxin-7-Q75 induced apoptotic death of cultured cerebellar neurons by downregulating Bcl-xL expression and activating mitochondrial apoptotic cascade. Mutant polyglutamine-expanded proteins are believed to impair the proteolytic function of ubiquitin-proteasome system by sequestering components of proteasomes. Proteasome degradation of IκBα permits nuclear translocation of NF-κB and is required for continuous NF-κB activity, which supports the survival of cultured cerebellar neurons by inducing Bcl-xL expression. Thus, we tested the hypothesis that mutant ataxin-7-Q75 causes proteasome dysfunction and impairs NF-κB activity, leading to reduced Bcl-xL expression, caspase activation and cerebellar neuronal death. EMSA assays indicate that DNA-binding activity of NF-κB was significantly decreased in cerebellar neurons expressing ataxin-7-Q75. Similar to mutant ataxin-7-Q75, NF-κB inhibitor APEQ induced cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Mutant ataxin-7-Q75 inhibited the proteolytic activity of proteasomes in cerebellar neurons. Proteasome inhibitor MG132 also caused cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Both ataxin-7-Q75 and MG132 caused the cytosolic accumulation of IκBα in cerebellar neurons. Mutant ataxin-7-Q75 or MG132 increased the cytosolic level of NF-κB p65 and decreased the nuclear NF-κB p65 level. Our study provides the evidence that polyglutamine-expanded ataxin-7-Q75 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons.
原文英語
頁(從 - 到)573-581
頁數9
期刊Cellular Signalling
19
發行號3
DOIs
出版狀態已發佈 - 三月 2007
對外發佈Yes

指紋

Proteasome Endopeptidase Complex
Neurons
Caspase 9
Proteasome Inhibitors
Ataxin-7
polyglutamine
Caspases
Ubiquitin
Down-Regulation
DNA
benzyloxycarbonylleucyl-leucyl-leucine aldehyde

ASJC Scopus subject areas

  • Cell Biology

引用此文

Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons. / Wang, Hung Li; He, Cai Ying; Chou, An Hsun; Yeh, Tu Hsueh; Chen, Ying Ling; Li, Allen Hon Lun.

於: Cellular Signalling, 卷 19, 編號 3, 03.2007, p. 573-581.

研究成果: 雜誌貢獻文章

Wang, Hung Li ; He, Cai Ying ; Chou, An Hsun ; Yeh, Tu Hsueh ; Chen, Ying Ling ; Li, Allen Hon Lun. / Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons. 於: Cellular Signalling. 2007 ; 卷 19, 編號 3. 頁 573-581.
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title = "Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons",
abstract = "Our recent study indicated that polyglutamine-expanded ataxin-7-Q75 induced apoptotic death of cultured cerebellar neurons by downregulating Bcl-xL expression and activating mitochondrial apoptotic cascade. Mutant polyglutamine-expanded proteins are believed to impair the proteolytic function of ubiquitin-proteasome system by sequestering components of proteasomes. Proteasome degradation of IκBα permits nuclear translocation of NF-κB and is required for continuous NF-κB activity, which supports the survival of cultured cerebellar neurons by inducing Bcl-xL expression. Thus, we tested the hypothesis that mutant ataxin-7-Q75 causes proteasome dysfunction and impairs NF-κB activity, leading to reduced Bcl-xL expression, caspase activation and cerebellar neuronal death. EMSA assays indicate that DNA-binding activity of NF-κB was significantly decreased in cerebellar neurons expressing ataxin-7-Q75. Similar to mutant ataxin-7-Q75, NF-κB inhibitor APEQ induced cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Mutant ataxin-7-Q75 inhibited the proteolytic activity of proteasomes in cerebellar neurons. Proteasome inhibitor MG132 also caused cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Both ataxin-7-Q75 and MG132 caused the cytosolic accumulation of IκBα in cerebellar neurons. Mutant ataxin-7-Q75 or MG132 increased the cytosolic level of NF-κB p65 and decreased the nuclear NF-κB p65 level. Our study provides the evidence that polyglutamine-expanded ataxin-7-Q75 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons.",
keywords = "Ataxin-7, Cerebellum, NF-κB, Polyglutamine-expanded ataxin-7, Proteasome, Spinocerebellar ataxia type 7",
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T1 - Polyglutamine-expanded ataxin-7 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons

AU - Wang, Hung Li

AU - He, Cai Ying

AU - Chou, An Hsun

AU - Yeh, Tu Hsueh

AU - Chen, Ying Ling

AU - Li, Allen Hon Lun

PY - 2007/3

Y1 - 2007/3

N2 - Our recent study indicated that polyglutamine-expanded ataxin-7-Q75 induced apoptotic death of cultured cerebellar neurons by downregulating Bcl-xL expression and activating mitochondrial apoptotic cascade. Mutant polyglutamine-expanded proteins are believed to impair the proteolytic function of ubiquitin-proteasome system by sequestering components of proteasomes. Proteasome degradation of IκBα permits nuclear translocation of NF-κB and is required for continuous NF-κB activity, which supports the survival of cultured cerebellar neurons by inducing Bcl-xL expression. Thus, we tested the hypothesis that mutant ataxin-7-Q75 causes proteasome dysfunction and impairs NF-κB activity, leading to reduced Bcl-xL expression, caspase activation and cerebellar neuronal death. EMSA assays indicate that DNA-binding activity of NF-κB was significantly decreased in cerebellar neurons expressing ataxin-7-Q75. Similar to mutant ataxin-7-Q75, NF-κB inhibitor APEQ induced cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Mutant ataxin-7-Q75 inhibited the proteolytic activity of proteasomes in cerebellar neurons. Proteasome inhibitor MG132 also caused cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Both ataxin-7-Q75 and MG132 caused the cytosolic accumulation of IκBα in cerebellar neurons. Mutant ataxin-7-Q75 or MG132 increased the cytosolic level of NF-κB p65 and decreased the nuclear NF-κB p65 level. Our study provides the evidence that polyglutamine-expanded ataxin-7-Q75 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons.

AB - Our recent study indicated that polyglutamine-expanded ataxin-7-Q75 induced apoptotic death of cultured cerebellar neurons by downregulating Bcl-xL expression and activating mitochondrial apoptotic cascade. Mutant polyglutamine-expanded proteins are believed to impair the proteolytic function of ubiquitin-proteasome system by sequestering components of proteasomes. Proteasome degradation of IκBα permits nuclear translocation of NF-κB and is required for continuous NF-κB activity, which supports the survival of cultured cerebellar neurons by inducing Bcl-xL expression. Thus, we tested the hypothesis that mutant ataxin-7-Q75 causes proteasome dysfunction and impairs NF-κB activity, leading to reduced Bcl-xL expression, caspase activation and cerebellar neuronal death. EMSA assays indicate that DNA-binding activity of NF-κB was significantly decreased in cerebellar neurons expressing ataxin-7-Q75. Similar to mutant ataxin-7-Q75, NF-κB inhibitor APEQ induced cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Mutant ataxin-7-Q75 inhibited the proteolytic activity of proteasomes in cerebellar neurons. Proteasome inhibitor MG132 also caused cerebellar neuronal death by decreasing Bcl-xL expression and activating caspase-9. Both ataxin-7-Q75 and MG132 caused the cytosolic accumulation of IκBα in cerebellar neurons. Mutant ataxin-7-Q75 or MG132 increased the cytosolic level of NF-κB p65 and decreased the nuclear NF-κB p65 level. Our study provides the evidence that polyglutamine-expanded ataxin-7-Q75 decreases nuclear translocation of NF-κB p65 and impairs NF-κB activity by inhibiting proteasome activity of cerebellar neurons.

KW - Ataxin-7

KW - Cerebellum

KW - NF-κB

KW - Polyglutamine-expanded ataxin-7

KW - Proteasome

KW - Spinocerebellar ataxia type 7

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DO - 10.1016/j.cellsig.2006.08.006

M3 - Article

C2 - 17005371

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