2006 Fiscal Year Final Research Report Summary
Molecular pathology for down-regulation of erythroid-specific genes in prion diseases
| Project/Area Number |
16208030
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied veterinary science
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| Research Institution | Hokkaido University |
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Principal Investigator |
INABA Mutsumi Hokkaido University, Graduate School of Veterinary Medicine, Professor, 大学院獣医学研究科, 教授 (00183179)
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| Co-Investigator(Kenkyū-buntansha) |
HORIUCHI Motohiro Hokkaido University, Graduate School of Veterinary Medicine., Professor, 大学院獣医学研究科, 教授 (30219216)
INANAMI Osamu Hokkaido University, Graduate School of Veterinary Medicine, Associate Professor, 大学院獣医学研究科, 助教授 (10193559)
UMEMURA Takashi Hokkaido University, Graduate School of Veterinary Medicine, Professor, 大学院獣医学研究科, 教授 (00151936)
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| Project Period (FY) |
2004 – 2006
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| Keywords | prion diseases / molecular diagnosis / hematopoietic precursor cells / AHSP / cytokine / transcription regulation / zoonosis / cattle |
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| Research Abstract |
AHSP is an erythroid-specific molecular chaperone that stabilizes newly synthesised a-globin. Previous studies demonstrated that mRNA levels of AHSP were specifically reduced in hematopoietic tissues of prion-infected animals. The purpose of the present study is to clarify the mechanism for down-regulation of AHSP transcription. A series of truncation and mutation analyses on 2.5-kb 5' upstream region of the AHSP gene in MELhide8 cells and electrophoretic mobility shift assay showed that the minimal 5'-promoter region located at-328-286 to the translation initiation site including a GATA binding motif. Either of two upstream GATA elements at-403 and-381 enhanced reporter gene transcription only in the presence of the minimal GATA element described above. These findings indicate that an erythroid-specific transcription factor GATA-1 is essential to AHSP gene expression and suggest that the down-regulation of AHSP involves changes in GATA-1 transcriptional activation. There was no significant change in gene expression of AHSP, a-globin, b-globin, GATA-1, EKLF, and NF-E2 in MELhide8 cells when the cells were incubated with brain homogenates from scrapie-infected mice for up to 120 hours. Moreover, MELhide8 cells exhibited no accumulation of PrPsc even after 16 passages. These data demonstrated that Prrc has no direct effect on AHSP gene expression in erythroid cells. Instead, IL-6 significantly and IL-1β weakly reduced the expression of AHSP mRNA levels and the AHSP promoter-reporter gene expression in MELhide8 cells in a dose-dependent manner. The reduction was recovered in the presence of the inhibitor of the STAT3 pathway, suggesting that the signal transduction of an inflammatory cytokine IL-6 through STAT3 pathway would modulate GATA-1/AHSP promoter interaction and subsequently causes down-regulation of the AHSP gene.
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[Journal Article] Ubiquitylation-independent ER-associated degradation of an AEl mutant associated with dominant hereditary spherocytosis in cattle.2006
Author(s)
Ito, D., Koshino, I., Arashiki, N., Adachi, H., Tomihari, M., Tamahara, S., Kurogi, K., Amano, T., Ono, K., Inaba, M.
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Journal Title
Journal of Cell Science 119
Pages: 3602-3612
Description
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[Journal Article] Genetic diagnosis of band 3 deficiency and sexing in bovine preimplantation embryos.2006
Author(s)
Kageyama, S., Hirayama, H., Moriyasu, S., Inaba, M., Ito, D., Ohta, H., Sawai, K., Minamihashi, A., Onoe, S.
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Journal Title
Journal of Veterinary Medical Science 68
Pages: 319-323
Description
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[Journal Article] Identification of pH-sensitive regions in the mouse prion by the cysteine-scanning spin-labeling ESR technique.2006
Author(s)
Watanabe, Y., Watanabe, Y., Inanami, 0., Horiuchi, M., Hiraoka, W., Shimoyama, Y., Inagaki, F., Kuwabara, M.
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Journal Title
Biochemical and Biophysical Research Communications 350
Pages: 549-556
Description
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[Journal Article] Inhibition of PrPSc formation by synthetic 0-sufated glycopyranosides and their polymers.2006
Author(s)
Yamaguchi, S., Nishida, Y., Sasaki, K., Kambara, M., Kim, C.-L., Ishiguro, N., Nagatsuka, T., Uzawa, H., Horiuchi, M.
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Journal Title
Biochemical and Biophysical Research Communications 349
Pages: 485-491
Description
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