دورية أكاديمية
Quiescent fibroblasts are protected from proteasome inhibition-mediated toxicity.
| العنوان: | Quiescent fibroblasts are protected from proteasome inhibition-mediated toxicity. |
|---|---|
| المؤلفون: | Legesse-Miller A; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA., Raitman I, Haley EM, Liao A, Sun LL, Wang DJ, Krishnan N, Lemons JM, Suh EJ, Johnson EL, Lund BA, Coller HA |
| المصدر: | Molecular biology of the cell [Mol Biol Cell] 2012 Sep; Vol. 23 (18), pp. 3566-81. Date of Electronic Publication: 2012 Aug 08. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Cell Biology Country of Publication: United States NLM ID: 9201390 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1939-4586 (Electronic) Linking ISSN: 10591524 NLM ISO Abbreviation: Mol Biol Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Cell Biology, c1992- |
| مواضيع طبية MeSH: | Fibroblasts/*drug effects , Fibroblasts/*metabolism , Leupeptins/*pharmacology , Proteasome Endopeptidase Complex/*metabolism, 2-Methoxyestradiol ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; Estradiol/analogs & derivatives ; Estradiol/pharmacology ; Fibroblasts/cytology ; Flow Cytometry ; Foreskin/cytology ; Humans ; Immunoblotting ; Macrolides/pharmacology ; Male ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Oligonucleotide Array Sequence Analysis ; Sequestosome-1 Protein ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; Transcriptome/drug effects ; Transcriptome/genetics ; Ubiquitin/genetics ; Ubiquitin/metabolism |
| مستخلص: | Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition-mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition-induced cytotoxicity. |
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| معلومات مُعتمدة: | K01 CA128887 United States CA NCI NIH HHS; P50 GM071508 United States GM NIGMS NIH HHS; 1RC1 CA147961-01 United States CA NCI NIH HHS; RC1 CA147961 United States CA NCI NIH HHS; P30 CA072720 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Adaptor Proteins, Signal Transducing) 0 (Cysteine Proteinase Inhibitors) 0 (Leupeptins) 0 (Macrolides) 0 (Mitochondrial Proteins) 0 (SQSTM1 protein, human) 0 (Sequestosome-1 Protein) 0 (Ubiquitin) 11062-77-4 (Superoxides) 4TI98Z838E (Estradiol) 6I2QW73SR5 (2-Methoxyestradiol) 88899-55-2 (bafilomycin A1) EC 1.15.1.1 (Superoxide Dismutase) EC 3.4.25.1 (Proteasome Endopeptidase Complex) RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) |
| تواريخ الأحداث: | Date Created: 20120810 Date Completed: 20130304 Latest Revision: 20211021 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC3442405 |
| DOI: | 10.1091/mbc.E12-03-0192 |
| PMID: | 22875985 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1939-4586 |
|---|---|
| DOI: | 10.1091/mbc.E12-03-0192 |