Nuclear effects of ethanol-induced proteasome inhibition in
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firstname.lastname@example.org World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.1163 © 2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol 2009 March 14; 15(10): 1163-1167
Natalia A Osna, MD, PhD, Series Editor
Fawzia Bardag-Gorce, Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center, 1124 W. Carson St.
Torrance, CA 90502, United States
Author contibutions: Bardag-Gorce F wrote this review.
Supported by The NIH/NIAAA 8116 grant
Correspondence to: Fawzia Bardag-Gorce, PhD, The
Los Angeles Biomedical Research Institute at Harbor-UCLA
Medical Center, 1124 W. Carson St. Torrance, CA 90502,
United States. email@example.com
Telephone: +1-310-2221846 Fax: +1-310-2223614
Received: December 17, 2008 Revised: February 16, 2009
Accepted: February 23, 2009
Published online: March 14, 2009
Alcohol ingestion causes alteration in several cellular
mechanisms, and leads to inflammation, apoptosis,
immunological response defects, and fibrosis. These
phenomena are associated with significant changes
in the epigenetic mechanisms, and subsequently,
to liver cell memory. The ubiquitin-proteasome
pathway is one of the vital pathways in the cell that
becomes dysfunctionial as a result of chronic ethanol
consumption. Inhibition of the proteasome activity
in the nucleus causes changes in the turnover of
transcriptional factors, histone modifying enzymes,
and therefore, affects epigenetic mechanisms.
Alcohol consumption has been associated with an
increase in histone acetylation and a decrease in
histone methylation, which leads to gene expression
changes. DNA and histone modifications that result
from ethanol-induced proteasome inhibition are key
players in regulating gene expression, especially genes
involved in the cell cycle, immunological responses,
and metabolism of ethanol. The present review
highlights the consequences of ethanol-induced
proteasome inhibition in the nucleus of liver cells that
are chronically exposed to ethanol.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Alcohol liver injury; Proteasome inhibition;
Peer reviewer: Maria Concepción Gutiérrez-Ruiz, PhD,
Departamento de Ciencias de la Salud, Universidad Autónoma
Metropolitana-Iztapalapa, DCBS, Av San Rafael Atlixco 186,
Colonia Vicentina, México, DF 09340, México
Bardag-Gorce F. Nuclear effects of ethanol-induced proteasome
inhibition in liver cells. World J Gastroenterol 2009; 15(10):
1163-1167 Available from: URL: http://www.wjgnet.
com/1007-9327/15/1163.asp DOI: http://dx.doi.org/10.3748/
Proteasomes of mammalian cells exhibit a complex
heterogeneity. Different proteasome variants exist
and perform subtle activities. The 20S proteasome
catalytic core binds to different activators (19S, 11S
and PA200), and the resulting complexes perform
specific functions, such as ATP-ubiquitin proteolysis,
immunological response, cell cycle regulation, nuclear
factor (NF) κB activation, response to hypoxia, and
transcription. Upon immune response, or interferon
(IFN)γ treatment, the three catalytic subunits, β1, β2
and β5, are replaced by three different subunits, LMP2,
LMP7 and MECL-1, respectively, which form the
immunoproteasome. Several chemical compounds,
proteins and regulatory complexes, function as activators
or inhibitors of the catalytic core 20S proteasome.
Some of them are termed gate-openers because they
provoke the opening of the gate at the alpha-type
subunits of the 20S proteasome, and facilitate the
access of designated proteins to be degraded to the
catalytic chamber formed by the beta-type subunits.
The best known of these activators are the regulatory
complex 19S, which is involved in the ubiquitin-
proteasome pathway (UPP), the PA28α/β and PA28γ
complexes, which, among other functions, are important
for the generation of epitope peptides presented to the
major histocompatibility complex, and PA200, which
is implicated in DNA repair. Recently, the hybrid form
of the 26S proteasome, which contains both 19S and
PA28 complexes associated at the two opposite sides
of the 20S core particle, has also been characterized,
and other activators and proteins that modulate the
proteasome activity are yet to be discovered.
As complex as is the UPP, it does not work alone.
These regulatory complexes and proteasome interacting
proteins (PIPs) complement the UPP to perform
specific functions. Proteasome failure occurs in the liver
cells because chronic ethanol exposure interferes with