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(Received for publication, September 3, 1996, and in revised form, December 24, 1996)
From the The accumulation of misfolded proteins in the
cytosol leads to increased expression of heat-shock proteins, while
accumulation of such proteins in the endoplasmic reticulum (ER)
stimulates the expression of many ER resident proteins, most of which
function as molecular chaperones. Recently, inhibitors of the
proteasome have been identified that can block the rapid degradation of
abnormal cytosolic and ER-associated proteins. We therefore tested
whether these agents, by causing the accumulation of abnormal proteins, might stimulate the expression of cytosolic heat-shock proteins and/or
ER molecular chaperones and thereby induce thermotolerance. Exposure of
Madin-Darby canine kidney cells to various proteasome inhibitors,
including the peptide aldehydes (MG132, MG115,
N-acetyl-leucyl-leucyl-norleucinal) and lactacystin,
inhibited the degradation of short-lived proteins and increased
markedly the levels of mRNAs encoding cytosolic heat-shock proteins
(Hsp70, polyubiquitin) and ER chaperones (BiP, Grp94, ERp72), as shown
by Northern blot analysis. However, inhibitors of cysteine proteases
(E64), serine proteases (leupeptin), or metalloproteases
(1,10-phenanthroline) had no effect on the levels of these mRNAs.
The relative efficacies of the peptide aldehyde inhibitors in inducing
these mRNAs correlated with their potencies against the proteasome.
Furthermore, reduction of the aldehyde group of MG132 decreased its
inhibitory effect on proteolysis and largely prevented the induction of
these mRNAs. Although treatment with the proteasome inhibitors
caused rapid increases in mRNA levels (as early as 2 h after
treatment with MG132), the inhibitors did not detectably affect total
protein synthesis, total protein secretion, ER morphology, or the
retention of ER-lumenal proteins, even after 18 h of treatment.
Together, the findings suggest that inhibition of proteasome function
induces heat-shock proteins and ER chaperones due to the accumulation
of sufficient amounts of abnormal proteins and/or the inhibition of
degradation of a key regulatory factor (e.g. heat-shock
factor). Since expression of heat-shock proteins can protect cells from
thermal injury, we tested whether the proteasome inhibitors might also
confer thermotolerance. Treatment of cells with MG132 for as little as 2 h, markedly increased the survival of cells subjected to high temperatures (up to 46 °C). Thus, these agents may have applications in protecting against cell injury.
Volume 272, Number 14,
Issue of April 4, 1997
pp. 9086-9092
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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Renal Division,
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