کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8324787 | 1539922 | 2012 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Multiple ways to die: Delineation of the unfolded protein response and apoptosis induced by Surfactant Protein C BRICHOS mutants
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کلمات کلیدی
eGFPSP-CPAGESDSDMEMPBSER stress - استرس استpolyacrylamide gel electrophoresis - الکتروفورز ژل پلی آکریل آمیدInterstitial lung disease - بیماری ریه بینابینیApoptosis - خزان یاختهایsodium dodecylsulfate - سدیم دودسیل سولفاتendoplasmic reticulum - شبکه آندوپلاسمی Phosphate buffered saline - فسفات بافر شورpolymerase chain reaction - واکنش زنجیره ای پلیمرازPCR - واکنش زنجیرهٔ پلیمرازUnfolded protein response - پاسخ پروتئین آشکارenhanced green fluorescent protein - پروتئین فلورسنت سبز افزایش یافته است
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Epithelial cell dysfunction is now recognized as an important mechanism in the pathogenesis of interstitial lung diseases. Surfactant Protein C (SP-C), an alveolar type II cell specific protein, has contributed to this concept with the observation that heterozygous expression of SFTPC gene mutations are associated with chronic interstitial lung disease. We have shown that transient expression of aggregation prone mutant SP-C isoforms (SP-C BRICHOS) destabilize ER quality control mechanisms resulting in the intracellular accumulation of aggregating propeptide, inhibition of the ubiquitin/proteasome system, and activation of apoptosis. The goal of the present study was to define signaling pathways linking the unfolded protein response (UPR) and subsequent ER stress with intrinsic apoptosis events observed following mutant SP-C expression. In vitro expression of the SP-C BRICHOS mutant, SP-CÎexon4, was used as a model system. Here we show stimulation of a broad ER stress response in both transfected A549 and HEK293 cells with activation of all 3 canonical sensing pathways, IRE1/XBP-1, ATF6, and PERK/eIF2α. SP-CÎexon4 expression also resulted in activation of caspase 3, but failed to stimulate expression of the apoptosis mediating transcription factors ATF4/CHOP. However, inhibition of either caspase 4 or c-jun kinase (JNK) each blocked caspase 3 mediated cell death. Taken together, these results suggest that expression of SP-C BRICHOS mutants induce apoptosis through multiple UPR signaling pathways, and provide new therapeutic targets for the amelioration of ER stress induced cytotoxicity observed in fibrotic lung remodeling.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 44, Issue 1, January 2012, Pages 101-112
Journal: The International Journal of Biochemistry & Cell Biology - Volume 44, Issue 1, January 2012, Pages 101-112
نویسندگان
Jean Ann Maguire, Surafel Mulugeta, Michael F. Beers,