| Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. | |
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MedLine Citation:
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PMID: 10562303 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Insulin deficiency (e.g., in acute diabetes or fasting) is associated with enhanced protein breakdown in skeletal muscle leading to muscle wasting. Because recent studies have suggested that this increased proteolysis is due to activation of the ubiquitin-proteasome (Ub-proteasome) pathway, we investigated whether diabetes is associated with an increased rate of Ub conjugation to muscle protein. Muscle extracts from streptozotocin-induced insulin-deficient rats contained greater amounts of Ub-conjugated proteins than extracts from control animals and also 40-50% greater rates of conjugation of (125)I-Ub to endogenous muscle proteins. This enhanced Ub-conjugation occurred mainly through the N-end rule pathway that involves E2(14k) and E3alpha. A specific substrate of this pathway, alpha-lactalbumin, was ubiquitinated faster in the diabetic extracts, and a dominant negative form of E2(14k) inhibited this increase in ubiquitination rates. Both E2(14k) and E3alpha were shown to be rate-limiting for Ub conjugation because adding small amounts of either to extracts stimulated Ub conjugation. Furthermore, mRNA for E2(14k) and E3alpha (but not E1) were elevated 2-fold in muscles from diabetic rats, although no significant increase in E2(14k) and E3alpha content could be detected by immunoblot or activity assays. The simplest interpretation of these results is that small increases in both E2(14k) and E3alpha in muscles of insulin-deficient animals together accelerate Ub conjugation and protein degradation by the N-end rule pathway, the same pathway activated in cancer cachexia, sepsis, and hyperthyroidism. |
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Authors:
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S H Lecker; V Solomon; S R Price; Y T Kwon; W E Mitch; A L Goldberg |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 104 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 1999 Nov |
Date Detail:
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Created Date: 1999-12-09 Completed Date: 1999-12-09 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1411-20 Citation Subset: AIM; IM; S |
Affiliation:
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Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cysteine Endopeptidases / genetics*, metabolism* Diabetes Mellitus, Experimental / genetics*, metabolism* Humans Male Multienzyme Complexes / genetics*, metabolism* Muscle Proteins / metabolism* Proteasome Endopeptidase Complex RNA, Messenger / genetics Rabbits Rats Reference Values Reticulocytes / metabolism Transcription, Genetic Ubiquitins / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK50740/DK/NIDDK NIH HHS; GM46147/GM/NIGMS NIH HHS; HL45317/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Multienzyme Complexes; 0/Muscle Proteins; 0/RNA, Messenger; 0/Ubiquitins; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex |
| Investigator | |
Investigator/Affiliation:
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A L Goldberg / Harvard Med Sch, Boston, MA |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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