Document Detail


Impaired methylation as a novel mechanism for proteasome suppression in liver cells.
MedLine Citation:
PMID:  20026058     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The proteasome is a multi-catalytic protein degradation enzyme that is regulated by ethanol-induced oxidative stress; such suppression is attributed to CYP2E1-generated metabolites. However, under certain conditions, it appears that in addition to oxidative stress, other mechanisms are also involved in proteasome regulation. This study investigated whether impaired protein methylation that occurs during exposure of liver cells to ethanol, may contribute to suppression of proteasome activity. We measured the chymotrypsin-like proteasome activity in Huh7CYP cells, hepatocytes, liver cytosols and nuclear extracts or purified 20S proteasome under conditions that maintain or prevent protein methylation. Reduction of proteasome activity of hepatoma cell and hepatocytes by ethanol or tubercidin was prevented by simultaneous treatment with S-adenosylmethionine (SAM). Moreover, the tubercidin-induced decline in proteasome activity occurred in both nuclear and cytosolic fractions. In vitro exposure of cell cytosolic fractions or highly purified 20S proteasome to low SAM:S-adenosylhomocysteine (SAH) ratios in the buffer also suppressed proteasome function, indicating that one or more methyltransferase(s) may be associated with proteasomal subunits. Immunoblotting a purified 20S rabbit red cell proteasome preparation using methyl lysine-specific antibodies revealed a 25kDa proteasome subunit that showed positive reactivity with anti-methyl lysine. This reactivity was modified when 20S proteasome was exposed to differential SAM:SAH ratios. We conclude that impaired methylation of proteasome subunits suppressed proteasome activity in liver cells indicating an additional, yet novel mechanism of proteasome activity regulation by ethanol.
Authors:
Natalia A Osna; Ronda L White; Terrence M Donohue; Michael R Beard; Dean J Tuma; Kusum K Kharbanda
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-12-21
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  391     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-27     Completed Date:  2010-03-08     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1291-6     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
Affiliation:
Liver Study Unit, The Omaha Veterans Affairs (VA) Medical Center, Omaha, NE 68105, USA. nosna@UNMC.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimetabolites, Antineoplastic / pharmacology
Cell Line, Tumor
Chymotrypsin / metabolism
Ethanol / pharmacology
Humans
Liver / drug effects,  enzymology*
Methylation
Mice
Mice, Inbred C57BL
Proteasome Endopeptidase Complex / drug effects,  metabolism*
Rabbits
S-Adenosylhomocysteine / metabolism,  pharmacology
S-Adenosylmethionine / metabolism,  pharmacology
Tubercidin / pharmacology
Grant Support
ID/Acronym/Agency:
R21 AA017232-01A2/AA/NIAAA NIH HHS; R21 AA017296-02/AA/NIAAA NIH HHS; R21AA017296/AA/NIAAA NIH HHS; R21AA01732/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 29908-03-0/S-Adenosylmethionine; 64-17-5/Ethanol; 69-33-0/Tubercidin; 979-92-0/S-Adenosylhomocysteine; EC 3.4.21.1/Chymotrypsin; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

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