کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10747965 | 1050254 | 2016 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
4-Phenylbutyric acid reduces mutant-TGFBIp levels and ER stress through activation of ERAD pathway in corneal fibroblasts of granular corneal dystrophy type 2
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کلمات کلیدی
FACSTGFBIpXBP1S4-PBAATF6XBP1UPRRT-PCRPDIJnkERADBiP - BIPC/EBP homologous protein - C / EBP پروتئین همولوگc-Jun N-terminal kinase - C-Jun N-terminal kinaseIRE1α - IRE1ainositol-requiring enzyme 1α - آنزیم 1α مورد نیاز به آنزیم استER stress - استرس است4-phenylbutyric acid - اسید 4-فنیل بوتیریکendoplasmic reticulum-associated degradation - تداخل وابسته به شبکیه آندوپلاسمیCHOP - تکه کردنfluorescence-activated cell sorting - دسته بندی سلول های فعال فلورسنسendoplasmic reticulum - شبکه آندوپلاسمی activating transcription factor 6 - فعال کردن عامل رونویسی 6corneal fibroblasts - فیبروبلاست های قرنیهwild-type - نوع وحشیhomozygous - هموزیگوتreverse transcription-polymerase chain reaction - واکنش زنجیره ای رونویسی-پلیمراز معکوسUnfolded protein response - پاسخ پروتئین آشکارBinding immunoglobulin Protein - پروتئین ایمونوگلوبولین Bindingprotein disulfide isomerase - پروتئین دیسولفید ایزومرازPERK - پرک
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the transforming growth factor β-induced (TGFBI) gene. In GCD2 corneal fibroblasts, secretion of the accumulated mutant TGFBI-encoded protein (TGFBIp) is delayed via the endoplasmic reticulum (ER)/Golgi-dependent secretory pathway. However, ER stress as the pathogenic mechanism underlying GCD2 has not been fully characterized. The aim of this study was to confirm whether ER stress is linked to GCD2 pathogenesis and whether the chemical chaperone, 4-phenylbutyric acid (4-PBA), could be exploited as a therapy for GCD2. We found that the ER chaperone binding immunoglobulin protein (BiP) and the protein disulfide isomerase (PDI) were elevated in GCD2. Western bolt analysis also showed a significant increase in both the protein levels and the phosphorylation of the key ER stress kinases, inositol-requiring enzyme 1α (IRE1α) and double stranded RNA activated protein kinase (PKR)-like ER kinase, as well as in levels of their downstream targets, X box-binding protein 1 (XBP1) and activating transcription factor 4, respectively, in GCD2 corneal fibroblasts. GCD2 cells were found to be more susceptible to ER stress-induced cell death than were wild-type corneal fibroblasts. Treatment with 4-PBA considerably reduced the levels of BiP, IRE1α, and XBP1 in GCD2 cells; notably, 4-PBA treatment significantly reduced the levels of TGFBIp without change in TGFBI mRNA levels. In addition, TGFBIp levels were significantly reduced under ER stress and this reduction was considerably suppressed by the ubiquitin proteasome inhibitor MG132, indicating TGFBIp degradation via the ER-associated degradation pathway. Treatment with 4-PBA not only protected against the GCD2 cell death induced by ER stress but also significantly suppressed the MG132-mediated increase in TGFBIp levels under ER stress. Together, these results suggest that ER stress might comprise an important factor in GCD2 pathophysiology and that the effects of 4-PBA treatment might have important implications for the development of GCD2 therapeutics.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 477, Issue 4, 2 September 2016, Pages 841-846
Journal: Biochemical and Biophysical Research Communications - Volume 477, Issue 4, 2 September 2016, Pages 841-846
نویسندگان
Seung-il Choi, Eunhee Lee, Jang Bin Jeong, Begum Akuzum, Yong-Sun Maeng, Tae-im Kim, Eung Kweon Kim,