کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1990401 1540718 2009 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Mechanisms of nuclear vitamin D receptor resistance in Harvey-ras-transfected cells
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Mechanisms of nuclear vitamin D receptor resistance in Harvey-ras-transfected cells
چکیده انگلیسی

The hormone 1,25 dihydroxyvitamin D (1,25(OH)2D) binds to the nuclear vitamin D receptor (nVDR), which heterodimerizes with retinoid X receptor α (RXRα), and this complex interacts with specific response elements [vitamin D response elements (VDREs)] to regulate gene transcription. Previous results show a significant reduction in 1,25(OH)2D-induced nVDR transcriptional activity in fibroblast (C3H10T1/2) cells transfected with the Harvey ras gene (ras cells) compared with parental cells. The purpose of this study was to investigate the mechanisms by which the H-ras gene interferes with nVDR transcriptional activity. Similar to the ras cells, transcriptional activity of the nVDR was reduced following induction of the H-ras gene for 9 days. The ras cells expressed similar protein levels of RXRα with the parent cells, and overexpression of the wild-type RXRα plasmid did not restore 1,25(OH)2D-mediated nVDR activity in ras cells. Inhibiting activation of extracellular signal-regulated kinase (ERK1/2) had no effect on nVDR activity in ras cells. Furthermore, the binding of nVDR to VDREs was reduced in 1,25(OH)2D-treated ras cells. In addition, neither treatment of ras cells with an inhibitor (ketoconazole) of the 1,25(OH)2D degradative enzyme, 24-hydroxylase, nor the protein kinase C inhibitors, bisindoylmaleimide I and Gö 6976, had an effect on nVDR activity. In contrast, inhibition of phosphatidylinositol 3-kinase (PI3K) with LY294002 resulted in a 1.6-fold significant increase in the nVDR activity in the ras cells. Taken together, these results indicate that PI3K may, at least in part, mediate the suppression of the 1,25(OH)2D regulation of nVDR transcriptional activity by the H-ras gene, leading to reduced ability to associate with response elements.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The Journal of Nutritional Biochemistry - Volume 20, Issue 8, August 2009, Pages 629–637
نویسندگان
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