کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8716236 | 1587880 | 2018 | 28 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis
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کلمات کلیدی
PAAMGSK-3SCFCTGFTAZTGFβSSCNrf2EDN1MMPPI3KDMFPolyacrylamide - پلی آکریل آمیدAkt - آکتsystemic sclerosis - اسکلروز سیستمیکendothelin 1 - اندوتلین 1YAP - ایجادtransforming growth factor-β - تبدیل فاکتور رشد βdimethyl fumarate - دی متیل فوماراتConnective tissue growth factor - فاکتور رشد بافت همبندnuclear factor (erythroid-derived 2)-like 2 - فاکتور هسته ای (erythroid-derived 2) -like 2phosphatidylinositol 3 kinase - فسفاتیدیلینوزیتول 3 کینازmatrix metalloproteinase - ماتریکس متالوپروتئینازyes-associated protein - پروتئین مرتبط با بلهprotein kinase B - پروتئین کیناز Bhealthy control - کنترل سالم
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
امراض پوستی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment options. Fumaric acid esters, including dimethyl fumarate (DMF, Tecfidera; Biogen, Cambridge, MA), have shown therapeutic effects in several disease models, prompting us to determine whether DMF is effective as a treatment for SSc dermal fibrosis. We found that DMF blocks the profibrotic effects of transforming growth factor-β (TGFβ) in SSc skin fibroblasts. Mechanistically, we found that DMF treatment reduced nuclear localization of transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP) proteins via inhibition of the phosphatidylinositol 3 kinase/protein kinase B (Akt) pathway. In addition, DMF abrogated TGFβ/Akt1 mediated inhibitory phosphorylation of glycogen kinase 3β (GSK3β) and a subsequent β-transducin repeat-containing proteins (βTRCP) mediated proteasomal degradation of TAZ, as well as a corresponding decrease of TAZ/YAP transcriptional targets. Depletion of TAZ/YAP recapitulated the antifibrotic effects of DMF. We also confirmed the increase of TAZ/YAP in skin biopsies from patients with diffuse SSc. We further showed that DMF significantly diminished nuclear TAZ/YAP localization in fibroblasts cultured on a stiff surface. Importantly, DMF prevented bleomycin-induced skin fibrosis in mice. Together, our work demonstrates a mechanism of the antifibrotic effect of DMF via inhibition of Akt1/GSK3β/TAZ/YAP signaling and confirms a critical role of TAZ/YAP in mediating the profibrotic responses in dermal fibroblasts. This study supports the use of DMF as a treatment for SSc dermal fibrosis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Investigative Dermatology - Volume 138, Issue 1, January 2018, Pages 78-88
Journal: Journal of Investigative Dermatology - Volume 138, Issue 1, January 2018, Pages 78-88
نویسندگان
Tetsuo Toyama, Agnieszka P. Looney, Brendon M. Baker, Lukasz Stawski, Paul Haines, Robert Simms, Aleksander D. Szymaniak, Xaralabos Varelas, Maria Trojanowska,