Study of gene expression on toxicity of dioxin in cultured cells
| Project/Area Number |
11672231
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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 |
Environmental pharmacy
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| Research Institution | Nihon University |
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Principal Investigator |
TEZUKA Masakatsu College of Pharmacy, Professor, 薬学部, 教授 (00046294)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | TCDD / uPA mRNA / 3T3-L1 cells / adipocyte differentiation / clonal expansion / C / EBPα / PPARγ2 / p42 / p44 / Rbタンパク質 / p107 / Ahレセプター |
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| Research Abstract |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic compound that has recently attracted much attention as an environmental contaminant, elicits a variety of toxic responses. Most of the toxic effects of TCDD are thought to result from alteration of gene expression. In this study, we investigated the trans-acting factors involved in TCDD-dependent mRNA stabilization in a rat liver cytoplasm after a single dose administration of TCDD.UV-crosslinking study showed that the cytoplasmic protein of 50 kDa (p50) selectively recognized the 3' untranslated region of the urokinase-type plasminogen activator (uPA) mRNA.We also showed that the activation of p50 by TCDD is mediated through a protein phosphorylation cascade but not via de novo protein synthesis.
We previously reported that a level of arylhydrocarbon receptor (AhR) protein decreased with ongoing adipose differentiation in 3T3-L1 cells. The AhR is the receptor for TCDD and related compounds. Studies using a TCDD-resistant clone
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of 3T3-L1 cells suggested that the AhR may be involved in the negative regulation of adipose differentiation. To confirm this hypothesis, 3T3-L1 fibroblast cells were stably transfected with a vector expressing high levels of full length sense AhR mRNA, antisense AhR mRNA, or a control vector. Comparison of the differentiation potency of these clones with that of control cells showed that overexpression of the AhR suppressed morphological differentiation as well as inductionof adipocyte-related genes, whereas decreased expression of the AhR induced much greater morphological differentiation and expression of adipocyte-related genes. Activation of C/EBPα and PPARγ2 restored the ability of the AhR-overexpressing cells to differentiate. The cells overexpressing the AhR exhibited the higher p42/p44 MAPkinase activity compared with the control cells. We also showed that activation of the AhR slowed clonal expansion. These results strongly suggest that AhR is a negative regulator of adipose differentiation in 3T3-L1 cells. Less
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Report
(3 results)
Research Products
(2 results)
