Functional analysis of phospholipid-metabolizing enzyme signal transduction during early phase of cell death after ischemia
Project/Area Number |
22791745
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Single-year Grants |
Research Field |
Emergency medicine
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Research Institution | Yamagata University |
Principal Investigator |
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Project Period (FY) |
2010 – 2012
|
Project Status |
Completed (Fiscal Year 2012)
|
Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | DGK / 虚血 / イノシトールリン脂質 / ユビキチン / 細胞周期 / シグナル伝達 / ポリユビキチン化 / リン脂質代謝酵素 / cell cycle re-entry / Rb / phagocytosis / IQGAP / Rac1 / macrophage / ストレス / 神経細胞死 / 核-細胞質間輸送 / NAP |
Research Abstract |
In previous study, we demonstrated that diacylglycerol kinase DGKzeta which is distributed at nucleus in normal hippocampal neuron in vivo, is translocated to cytoplasm from nucleus by middle cerebral artery infarction in rat. But it is unclear that the mechanisms of ischemia induced translocation of DGKzeta and the physiological functions after localization in cytoplasm of DGKzeta. In this study, we demonstrated that transient exposure to excitotoxic concentration of glutamate led to cytoplasmic accumulation of DGKζ followed by its down-regulation. Results showed that DGKζ down-regulation was caused by proteolytic degradation through the ubiquitin.proteasome system UPSrather than transcriptional inhibition. DGKζ-deficient hippocampus exhibited a significant increase in Ser807811 phosphorylated retinoblastoma protein levels together with up-regulation of the expression of type D and E cyclins, indicative of cell cycle reentry. From a functional perspective, in vitro gene silencing of D
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GKzeta via specific siRNA enhanced DNA fragmentation in cultured neurons after glutamate exposure. At the organismal level, hippocam-pal neurons of DGKzeta-deficient mice showed vulnerability to kainate-induced seizures. In addition, nucleosome assembly pro-tein NAP1-like 1 NAP1L1and NAP1-like 4 NAP1L4are identified as novel DGKzeta binding partners. The molecular interaction of DGKzeta and NAP1Ls prohibits nuclear import of DGKzeta because binding of NAP1Ls to DGKzeta blocks import carrier proteins, Qip1 and NPI1, to interact with DGKzeta, leading to cytoplasmic tethering of DGKzeta. In addition, overexpression of NAP1Ls ex-erts a protective effect against doxorubicin-induced cytotoxicity. Additionally, we identified a small GTPase effector protein, IQGAP1, as a novel DGKzeta-associated complex protein. A bacterial endotoxin, lipopolysaccharide LPSfacilitated the complex formation in macrophages. RNA interference-mediated knockdown of DGKzeta or IQGAP1 impaired LPS-induced Rac1 activation. Primary macrophages derived from DGKzeta-mice attenuated LPS-induced phagocytosis of bacteria. DGKzeta is involved in IQGAP1Rac1-mediated phagocytosis upon LPS stimulation in macrophages. Less
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] DGKζ is degraded through the cytoplasmic ubiquitin-proteasome system under excitotoxic conditions, which causes neuronal apoptosis because of aberrant cell cycle reentry2012
Author(s)
Okada M, Hozumi Y, Tanaka T, Suzuki Y, Yanagida M, Araki Y, Evangelisti C, Yagisawa H, Topham MK, Martelli AM, Goto K.
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Journal Title
Cell Signal
Volume: 24
Issue: 8
Pages: 1573-82
DOI
Related Report
Peer Reviewed
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[Journal Article] NMDA receptor-mediated Ca(2+) influx triggers nucleocytoplasmic translocation of diacylglycerol kinase ζ under oxygen-glucose deprivation conditions, an in vitro model of ischemia, in rat hippocampal slices2012
Author(s)
Suzuki Y, Yamazaki Y, Hozumi Y, Okada M, Tanaka T, Iseki K, Ohta N, Aoyagi M, Fujii S, Goto K.
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Journal Title
Histochem CellBiol
Volume: 137
Issue: 4
Pages: 499-511
DOI
Related Report
Peer Reviewed
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[Journal Article] Targeting JNK for therapeutic depletion of stem-like glioblastoma cells2012
Author(s)
Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C
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Journal Title
Sci Rep
Volume: 2
Issue: 1
Pages: 516-516
DOI
Related Report
Peer Reviewed
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[Journal Article] NAP Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKζ by attenuating its association with importins2011
Author(s)
Okada M, Hozumi Y, Ichimura T, Tanaka T, Hasegawa H, Yamamoto M, Takahashi N, Iseki K, Yagisawa H, Shinkawa T, Isobe T, Goto K.
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Journal Title
Exp Cell Res
Volume: 317
Issue: 20
Pages: 2853-63
DOI
Related Report
Peer Reviewed
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