2010 Fiscal Year Final Research Report
Elucidation of novel molecular regulatory mechanisms underlying tyrosine hydroxylase functional expression and development of therapeutics for the CNS neurodegenerative disorders
| Project/Area Number |
20500331
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
YAMAKUNI Tohru 東北大学, 大学院・薬学研究科, 准教授 (30333793)
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| Co-Investigator(Renkei-kenkyūsha) |
KAKIZAKI Atsushi 岩手医科大学, 医学部, 研究員 (70458173)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 精神・神経疾患の病態と治療 |
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| Research Abstract |
V-1 is 13 kDa protein with four ankyrin-repeats for specific molecular interaction with CapZ, an actin capping protein, which was originally identified by us as a developmentally regulated protein in murine postnatal brains. Our recent in vitro and in vivo studies have demonstrated that V-1 can positively control gene transcription of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine biosynthesis, thereby promoting catecholamine production in catecholaminergic cells. In the present study, we tried to elucidate the molecular mechanism underlying control of TH gene expression by V-1 in PC12D cells, a rat adrenal pheochromocytoma cell line endogenously expressing TH protein, using siRNAs for V-1, CapZ and pref-1/DLK1, because the pref-1/DLK1 gene expression is observed to be up-regulated by V-1 in MC3T3-G2/PA6 cells, a mouse preadipocyte cell line. Knockdown of V-1 and CapZ with each siRNA for the both genes resulted in a decrease in TH protein level, accompanied by down-regulation of the expression of pref-1/DLK1 protein, whereas actin protein level showed no changes, as assayed by Western blot analyses. Consistently, it was shown that knockdown of pref-1/DLK1 caused decreased expression of TH protein. Moreover, TH gene transcription is decreased by knockdown of V-1, CapZ and pref-1/DLK1 with each of siRNAs for the three genes, when determined by reporter gene assay. These findings suggest that V-1 may control TH gene expression via pref-1/DLK1 protein in co-operation with CapZ, the actin cytoskeletal regulator, in the CNS catecholaminergic cells.
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Research Products
(21 results)
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[Journal Article] V-1, a Positive Regulator of Tyrosine Hydroxylase Gene Expression, Promotes Maitotoxin-and Palytoxin-induced Norepinephrine Secretion in PC12D Cells2010
Author(s)
Kakizaki A, Oka N, Tachikawa E, Miyate Y, Takahashi K, Yamamoto T, Taira E, Ohizumi Y, and Yamakuni T
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Journal Title
Pharmacometric
Volume: 78
Pages: 67-71
Peer Reviewed
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[Journal Article] Dual effects of nobiletin, a citrus polymethoxy flavone, on catecholamine secretion in cultured bovine adrenal medullary cells.2010
Author(s)
Zhang H, Toyohira Y, Ueno S, Shinohara Y, Itoh H, Furuno Y, Yamakuni T, Tsutsumi M, Takahashi K and Yanagihara N
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Journal Title
J. Neurochem.
Volume: 114
Pages: 1030-1038
Peer Reviewed
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[Journal Article] 4'-Demethlynobiletin, a bioactive metabolite of nobiletin enhancing PKA/ERK/CREB signaling, rescues learning impairment associated with NMDA receptor antagonism via stimulation of the ERK cascade.2009
Author(s)
Md. Al Rahim, Nakajima A., Saigusa D., Tetsu N., Maruyama Y., Shibuya, M., Yamakoshi H., Tomioka Y., Iwabuchi Y. Ohizumi Y. & Yamakuni T.
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Journal Title
Biochemistry
Volume: 48
Pages: 7713-7721
Peer Reviewed
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[Journal Article] Nobiletin, a citrus flavonoid, improves memory impairment and A. pathology in a transgenic mouse model of Alzheimer's disease.2008
Author(s)
Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T & Ohizumi Y
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Journal Title
J. Pharmacol. Exp. Ther.
Volume: 326
Pages: 739-744
Peer Reviewed
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[Journal Article] Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus.2008
Author(s)
Matsuzaki, K., Miyazaki, K., Sakai, S., Yawo, H., Nakata, N., Moriguchi, S., Fukunaga, K., Yokosuka, A., Sashida, Y., Mimaki, Y., Yamakuni T. & Yasushi Ohizumi, Y.
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Journal Title
Eur. J. Pharmacol
Volume: 578
Pages: 194-200
Peer Reviewed
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