Document Detail


Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats.
MedLine Citation:
PMID:  10562303     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
S H Lecker; V Solomon; S R Price; Y T Kwon; W E Mitch; A L Goldberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  104     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  1999-12-09     Completed Date:  1999-12-09     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1411-20     Citation Subset:  AIM; IM; S    
Affiliation:
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
DK50740/DK/NIDDK NIH HHS; GM46147/GM/NIGMS NIH HHS; HL45317/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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:
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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