کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5824079 | 1118402 | 2010 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
IL-4-mediated transcriptional regulation of human CYP2E1 by two independent signaling pathways
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کلمات کلیدی
NF-κBPI3KCyPIL-4Nuclear factor of activated T-cells cytoplasmic 1ELK1FOXO1IRSNFATc1IL-4RStat6MAPK - MAPKinsulin receptor substrate - انسولین بستر گیرندهchromatin immunoprecipitation - ایمن سازی کروماتینinterleukin-4 - اینترلوکین -4cytochrome P450 2E1 - سیتوکروم P450 2E1Cytochrome P450 - سیتوکروم پی۴۵۰Transcription factors - عوامل رونویسیnuclear factor kappa B - فاکتور هسته ای کاپا Bphosphoinositide-3-kinase - فسفونیوییدید-3-کینازTranscriptional activation - فعال سازی رونویسیSignal transducer and activator of transcription 6 - مبدل سیگنال و فعال کننده رونویسی 6Forkhead box protein O1 - پروتئین جعبه ی جعبه ای O1JAK - چگونهCHiP - چیپInterleukin-4 receptor - گیرنده اینترلوکین -4
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
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چکیده انگلیسی
Cytochrome P450 2E1 (CYP2E1), the alcohol-inducible member of the cytochrome P450 super family, plays an important role in both physiological and pathophysiological processes. The present study focused on the induction of human CYP2E1 transcription by the anti-inflammatory cytokine interleukin-4 (IL-4) in human hepatoma B16A2 cells and revealed that this regulation is mediated by two independent pathways. RNA interference and overexpression of STAT6, indicated that the JAK-STAT signaling pathway is involved in IL-4-dependent induction and mutagenesis revealed the presence of a STAT6 binding site in CYP2E1 proximal promoter region (â583/â574-bp). However, inhibition of the JAK-STAT6 pathway using JAK1 siRNA constructs could only partially inhibit the induction of CYP2E1 promoter constructs indicating the presence of a second IL-4 responsive element. Indeed by using a series of truncated CYP2E1 promoter constructs a second more distal IL-4 responsive element (â1604/â1428-bp) was identified, which was further shown to involve the activation of IRS1/2. This induction was dependent on the transcription factor NFATc1 as IL-4-induced CYP2E1 expression was altered by silencing or overexpressing NFATc1. A NFATc1 binding site was identified in the second distal IL-4 responsive element (â1551/â1545-bp) by chromatin immunoprecipitation (ChIP) analysis. Finally simultaneous siRNA-mediated down-regulation of both STAT6 and NFATc1 or mutation of both STAT6 and NFATc1 binding sites abolished the IL-4-dependent transcriptional induction of CYP2E1, demonstrating that both pathways are required for maximal activation. In conclusion, the present study indicates that the induction of CYP2E1 transcription by IL-4 is mediated through two independent parallel pathways, involving JAK-STAT6 and IRS1/2 and NFATc1.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 80, Issue 10, 15 November 2010, Pages 1592-1600
Journal: Biochemical Pharmacology - Volume 80, Issue 10, 15 November 2010, Pages 1592-1600
نویسندگان
Jue Wang, Yin Hu, Jana Nekvindova, Magnus Ingelman-Sundberg, Etienne P.A. Neve,