کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5506621 | 1400300 | 2016 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The Vascular Endothelial Growth Factor-A phosphorylates Murine Double Minute-2 on its Serine 166 via the Extracellular Signal-Regulated Kinase 1/2 and p90 Ribosomal S6 Kinase in primary human endothelial cells
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کلمات کلیدی
PI3KMitogen-activated protein kinase/extracellular signal-regulated kinase kinasep90RSKVEGF-AHIF-1αVEGFR2ERK1/2 - ERK1 / 2MAPK - MAPKMdm2 - MDM2Mitogen activated protein kinases - Mitogen فعال پروتئین کینازp90 ribosomal S6 kinase - S6 kinase ribosomal p90Angiogenesis - آنژیوژنزEndothelial cell - سلول های اندوتلیالhuman dermal microvascular endothelial cells - سلولهای اندوتلیال میکرواسکولی پوست انسانhypoxia inducible factor-1α - عامل القایی هیپوکسی 1αSkeletal muscle - عضله اسکلتیvascular endothelial growth factor-A - فاکتور رشد اندوتلیال عروق APhosphatidylinositol 3-kinase - فسفاتیدیلینواستیل 3-کینازMEK - مجاهدین خلقextracellular signal-regulated kinase 1/2 - کیناز 1/2 تنظیم سیگنال خارج سلولیvascular endothelial growth factor receptor 2 - گیرنده فاکتور رشد اندوتلیال عروقی 2
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Murine Double Minute-2 (Mdm2) has been identified as an essential regulator of skeletal muscle angiogenesis and the pro-angiogenic activity of endothelial cells. We have recently demonstrated that the pro-angiogenic Vascular Endothelial Growth Factor-A (VEGF-A) is a potent upstream regulator of Mdm2 phosphorylation on its Serine 166 (p-Ser166-Mdm2), a protein modification leading to an increase in endothelial cell migration. Here, we investigated the kinase signaling pathways that could be responsible for mediating VEGF-A-dependent Mdm2 phosphorylation. Incubation of primary human dermal microvascular endothelial cells with recombinant VEGF-A for 15Â min led to increased phosphorylation levels of VEGF-receptor-2, Mdm2, Akt, Extracellular Signal-Regulated Kinase 1/2 (ERK1/2), and p90 Ribosomal S6 Kinase (p90RSK) proteins. In addition to being linked to VEGF-A signaling, Akt, ERK1/2 and p90RSK have been shown to potentially lead to Mdm2 phosphorylation. We therefore next analyzed which of these kinases could be responsible for VEGF-A-dependent Mdm2 phosphorylation on Serine 166 by using kinase-specific pharmacological inhibitors. Inhibition of ERK1/2 phosphorylation by UO126 entirely abrogated the response of p-Ser166-Mdm2 to VEGF-A treatment, while Akt phosphorylation inhibition by wortmannin led to further elevations in p-Ser166-Mdm2. p90RSK has been identified as a potential candidate downstream of ERK1/2 that could induce Mdm2 Ser166 phosphorylation. Two independent p90RSK inhibitors, FMK and BI-D1870, each led to an entire loss of p-Ser166-Mdm2 responsiveness to VEGF-A. Taken together, our results demonstrate that VEGF-A driven Mdm2 phosphorylation on Ser166 is dependent on the ERK1/2/p90RSK signaling pathway in primary human endothelial cells, furthering our understanding of the complex relationship between Mdm2 and VEGF-A in a physiological context.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 478, Issue 4, 30 September 2016, Pages 1548-1554
Journal: Biochemical and Biophysical Research Communications - Volume 478, Issue 4, 30 September 2016, Pages 1548-1554
نویسندگان
Julian Aiken, Olivier Birot,