| Project/Area Number |
16390091
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SAKAI Juro The University of Tokyo, Research Center for Advanced Science and Technology, Specially Appointed Professor, 先端科学技術研究センター, 科学技術振興特任教員(特任教授) (80323020)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Toshiya The University of Tokyo, Research Center for Advanced Science and Technology, Specially Appointed Associate Professor, 先端科学技術研究センター, 産学官連携研究員(特任助教授) (20396930)
MAGOHRI Kenta The University of Tokyo, Research Center for Advanced Science and Technology, Specially Appointed Research Fellow, 先端科学技術研究センター, 産学官連携研究員(特任研究員) (90361683)
浅場 浩 東京大学, 先端科学技術研究センター, 科学技術振興特任教員 (20361678)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2004: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | LRP5 / Wnt signal / insulin / islet / obesity / PDX-1 / SOX6 / very low-density lipoprotein / WNT signal / Acetyl-CoA synthetase / Kruppel-like factor KLF15 |
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| Research Abstract |
A Wnt coreceptor low density lipoprotein receptor related protein 5 plays an essential role in bone accrual and eye development. In obesity-related insulin resistance, the pancreatic islets compensate for insulin resistance by increasing their secretory capacity or increasing islet cell mass. We investigated Wnt/β-catenin signal in pancreatic islet. Here, we report the identification of SOX6, a member of the HMG box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in the genetically obese ob/ob mice on a normal chow diet.
Overexpression of SOX6 decreased glucose stimulated insulin secretion (GSIS) which was accompanied by decreased ATP/ADP ratio, Ca^<2+> mobilization, proinsulin content and insulin genes expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented GSIS in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein : protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of the histones H3 and H4 in chromatin from the promoter for the insulin II gene suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. We also show that SOX6 overexpression results in a marked reduction in the expression of genes involved in mitochondrial oxidative phosphorylation, most of which were reciprocally up-regulated by PDX1 overexpression, suggesting that SOX6 may also act as a general co-repressor of other PDX1 dependent genes. Furthermore, we also demonstrated that SOX6 inhibits Wnt/β-catenin signaling pathway by physically interacting with β-catenin, recruiting histone deacetylase 1 and reduces INS-1 and NIH3T3 cell proliferation.
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