| Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic β-cells: protective role of p62-positive cytoplasmic inclusions. | |
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MedLine Citation:
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PMID: 20814419 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In type II diabetes (T2DM), there is a deficit in β-cells, increased β-cell apoptosis and formation of intracellular membrane-permeant oligomers of islet amyloid polypeptide (IAPP). Human-IAPP (h-IAPP) is an amyloidogenic protein co-expressed with insulin by β-cells. IAPP expression is increased with obesity, the major risk factor for T2DM. In this study we report that increased expression of human-IAPP led to impaired autophagy, due at least in part to the disruption of lysosome-dependent degradation. This action of IAPP to alter lysosomal clearance in vivo depends on its propensity to form toxic oligomers and is independent of the confounding effect of hyperglycemia. We report that the scaffold protein p62 that delivers polyubiquitinated proteins to autophagy may have a protective role against human-IAPP-induced apoptosis, apparently by sequestrating protein targets for degradation. Finally, we found that inhibition of lysosomal degradation increases vulnerability of β-cells to h-IAPP-induced toxicity and, conversely, stimulation of autophagy protects β-cells from h-IAPP-induced apoptosis. Collectively, these data imply an important role for the p62/autophagy/lysosomal degradation system in protection against toxic oligomer-induced apoptosis. |
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Authors:
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J F Rivera; T Gurlo; M Daval; C J Huang; A V Matveyenko; P C Butler; S Costes |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-03 |
Journal Detail:
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Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-14 Completed Date: 2011-05-31 Revised Date: 2012-03-01 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 415-26 Citation Subset: IM |
Affiliation:
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Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7073, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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metabolism* Animals Apoptosis / drug effects Autophagy* / drug effects Cell Line Heat-Shock Proteins / metabolism* Hyperglycemia / complications, metabolism, pathology Inclusion Bodies / drug effects, metabolism* Insulin-Secreting Cells / drug effects, metabolism*, pathology Islet Amyloid Polypeptide / chemistry, metabolism* Lysosomes / drug effects, metabolism* Mice Obesity / complications, metabolism, pathology Phagosomes / drug effects, metabolism Protective Agents / metabolism Protein Processing, Post-Translational / drug effects Protein Structure, Quaternary RNA, Small Interfering / metabolism Rats Signal Transduction / drug effects Sirolimus / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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DK059579/DK/NIDDK NIH HHS; R01 DK059579-11/DK/NIDDK NIH HHS; R01 DK059579-12/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Heat-Shock Proteins; 0/Islet Amyloid Polypeptide; 0/Protective Agents; 0/RNA, Small Interfering; 0/Sqstm1 protein, mouse; 0/Sqstm1 protein, rat; 53123-88-9/Sirolimus |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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