| Budget Amount *help |
¥537,940,000 (Direct Cost: ¥413,800,000、Indirect Cost: ¥124,140,000)
Fiscal Year 2007: ¥101,790,000 (Direct Cost: ¥78,300,000、Indirect Cost: ¥23,490,000)
Fiscal Year 2006: ¥101,400,000 (Direct Cost: ¥78,000,000、Indirect Cost: ¥23,400,000)
Fiscal Year 2005: ¥101,790,000 (Direct Cost: ¥78,300,000、Indirect Cost: ¥23,490,000)
Fiscal Year 2004: ¥119,990,000 (Direct Cost: ¥92,300,000、Indirect Cost: ¥27,690,000)
Fiscal Year 2003: ¥112,970,000 (Direct Cost: ¥86,900,000、Indirect Cost: ¥26,070,000)
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| Research Abstract |
In mammals, endoplasmic reticulum (ER) stress is sensed and transduced by three ubiquitously expressed transmembrane proteins in the ER (IRE1, PERK and ATF6). Physiological significance and roles of the IRE1 and PERK pathways have been clarified by making their knockout mice. We have succeeded in creating ATF6alpfa and ATF6beta knockout mice in this study. Thus, we now know phenotypes of knockout mice deficient in three major signal transduction pathways operating in the mammalian unfolded protein response (UPR).
Double knockout mice of ATF6alpfa and ATF6beta caused embryonic lethality at very early days (before embryonic day 8.5), which represents an earliest phenotype observed in knockout mice of UPR signaling molecules. ATF6alpfa was required for transcriptional induction of not only ER chaperones but also components of ER-associated degradation. Although it was previously shown that PERK knockout decreased the levels of ER chaperones, we were able to show that PERK knockout affected
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activation of ATF6. A group in USA reported previously that knockdown of ATF6alpfa and ATF6beta had almost no effect on induction of UPR target genes, however, we were able to show that it is not the case and that rather the ATF6 pathway is most important in the three signaling pathways.
In contrast to the IRE1 and PERK pathways, ATF6 itself is involved in all steps in signal transduction, from sensing ER stress to activation of transcription. By analyzing activation mechanisms of ATF6, we showed the presence of ATF6-escort protein through identification of its recognition sites and discovered a very interesting regulation, ER stress-induced reduction of disulfide bonds, that occurs in the oxidative ER.
We also showed that ATF6 is a transcription factor specializing in transcriptional induction of ER quality control proteins and that ATF6 has gained function in the UPR only in higher eukaryotes such as mammals. These constitute very important information in thinking of evolution of the UPR. Less
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