Analysis of knockout mouse of a brain-specific H^+ transporter ASPT.
| Project/Area Number |
14580763
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neuroscience in general
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| Research Institution | Gunma University |
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Principal Investigator |
SHIMOKAWA Noriaki Gunma University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (90235680)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | extracellular acidosis / ventral medullary surface of the medulla oblongata / acidosis-induced genes / nuclear transcription factors / c-Jun NH_2-terminal kinase / voltage-gated Ca^<2+> channels / H^+-sensitivity / Past-A / ASPT / H^+ sensitivity / Acidosis / JNK / Phosphorylation / Ca^<2+> / MafG-FosB / H^+ concentration / c-Jun / Glucose transporter / Hypercapnia / Glucose Transporter / Post-A / CIN85 / Cbl / EGF receptor / ubiquitination |
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| Research Abstract |
We describe the role of c-Jun NH_2-terminal kinase(JNK) in regulation of gene transcription after an increase in extracellular H^+. When cells were incubated in low pH medium, the promotion of JNK phosphorylation and c-Jun expression was clearly observed in cells in an extracellular pH-and time-dependent manner. Activation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) was extremely weak compared with that of JNK. An increase in extracellular H^+ led to enhanced nuclear translocation of phosphorylated JNK leading to augmentation of the transcriptional activity of c-Jun. Nimodipine, a blocker of voltage-gated Ca^<2+> ion channels, prevented the phosphorylation of JNK and expression of c-Jun in a dose-dependent manner. These results suggesta novel intracellular signalling pathway for H^+-induced c-Jun expression : an increase of extracellular H^+ induces JNK phosphorylation and c-Jun expression via partly extracellular Ca^<2+> influx through voltage-gated Ca^<2+> channels.
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We describe properties of gene expression, protein interaction and DNA binding activity of basic region leucine zipper(bZIP) transcription factor Maf and FosB during extracellular acidification. When cells were incubated with low pH medium, the expressions of small Maf proteins (MafG,MafK and MafF) and FosB were clearly increased in an extracellular pH-dependent manner and expressed transiently with a peak after 1-2 h after stimulation. Immunofluorescence and protein binding studies indicated that MafG was partially co-localized with FosB in the nucleus and MafG can form heterodimers with FosB at extracellular pH 7.40. Moreover, we found that MafG-FosB complexes are able to bind to AP-1 consensus sequence, TGACTCA. To investigate whether extracellular acidification influences to dimerization and DNA binding activity of MafG and FosB, extracellular pH of cultured cells was decreased from 7.40 to 6.80. The decrease in extracellular pH led to enhanced dimerization of MafG with FosB leading to augmentation of the DNA binding activity of the heterodimer to AP-1 consensus sequence. Moreover, extracellular acidification induces mRNA expression of matrix metalloproteinase-1, one of genes that are regulated by AP-1. These results suggest that MafG-FosB complexes are involved in transcriptional regulation in response to extracellular acidification. Less
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Research Products
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