کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2512192 1118322 2014 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Ceramide synthases CerS4 and CerS5 are upregulated by 17β-estradiol and GPER1 via AP-1 in human breast cancer cells
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Ceramide synthases CerS4 and CerS5 are upregulated by 17β-estradiol and GPER1 via AP-1 in human breast cancer cells
چکیده انگلیسی

Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2, -4, -5 and CerS6 promoter and 3′-UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERα/β) and MDA-MB-231 (ERβ) cells after 17β-estradiol treatment. Only the activities of CerS4 and CerS5 promoter Luc constructs, as well as CerS2- and CerS5-3′-UTR Luc constructs increased after estradiol treatment in MCF-7 cells, and this could be inhibited by the anti-estrogen fulvestrant. Co-transfection with the G protein-coupled estrogen receptor 1 (GPER1) also enhanced CerS2, CerS4 and CerS6 promoter activity whereas CerS5 promoter activity was inhibited in both cell lines. Promoter deletion and mutation constructs from CerS4 and CerS5 promoters revealed that estradiol and GPER1 mediate their effects on both promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos. At least we could show, that cell proliferation induced by estradiol could be blocked by co-treatment with Fumonisin B1, indicating that upregulation of CerS in breast cancer cells by estrogen is important for cell proliferation and possibly tumor development. In conclusion, our data highlight transcriptional and posttranscriptional mechanisms regulating CerS expression in human cells which provide the basis for further studies investigating the regulation of CerS expression and ceramide synthesis after diverse stimuli in physiological and pathophysiological processess.

Estradiol and GPER1 mediate their effects on CerS4 and CerS5 promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 92, Issue 4, 15 December 2014, Pages 577–589
نویسندگان
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