کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10768280 1050806 2005 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Synergistic activation of the murine gastrin promoter by oncogenic Ras and β-catenin involves SMAD recruitment
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Synergistic activation of the murine gastrin promoter by oncogenic Ras and β-catenin involves SMAD recruitment
چکیده انگلیسی
While Wnt and Ras signaling pathways are activated during progression of colorectal cancers, many of their important downstream targets remain to be elucidated. The gastrin gene encodes for a family of peptide growth factors that are commonly upregulated in colorectal neoplasia. Previously, we showed that the Wnt signaling pathway moderately stimulates the gastrin promoter. To determine whether Ras signaling can cooperate with Wnt signaling in transcriptional regulation of gastrin gene expression, we have analyzed the response of murine gastrin promoter-reporter gene constructs to combinations of oncogenic stimulation in transient transfection assays. We found a strong (25- to 40-fold) synergistic stimulation of the gastrin promoter by the combination of oncogenic β-catenin and K-ras overexpression. Deletion analysis localized the response element to an area between −140 and −110 bp upstream in the murine gastrin promoter. Electrophoretic mobility shift assays detected a complex containing β-catenin/TCF, AP1, and SMAD3/4 transcription factors that bound to a DNA element through AP1 and SMAD binding sites. Gastrin promoter activation could be further enhanced or suppressed by the co-expression of wild type SMAD4 or dominant negative mutant of SMAD4, respectively, and abrogated by the PI3K inhibitor, LY20004, but not by the MEK inhibitor, PD98059. Taken together, our data strongly suggest that oncogenic Wnt and Ras signaling pathways can synergistically induce gastrin expression, possibly contributing to neoplastic progression.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 336, Issue 1, 14 October 2005, Pages 190-196
نویسندگان
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