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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 269-274
Deregulation of the ubiquitin system and p53 proteolysis modify
the apoptotic response in B-CLL lymphocytes
Peggy Masdehors,
Hélène Merle-Béral,
Karim Maloum,
Satoshi Ömura,
Henri Magdelénat, and
Jozo Delic
From Laboratoire de Recherche Correspondant and Laboratoire de
Radiopathologie, Institut Curie, Paris; Service d'Hématologie
Biologique, Hôpital Pitié-Salpêtrière, Paris,
France; and Kitasato Institute, Tokyo, Japan.
We recently reported increased sensitivity of B-cell chronic
lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that
only specific not nonspecificproteasomal inhibitors can discriminate
between malignant and normal lymphocytes in inducing the apoptotic
death response. Indeed, lactacystin and its active metabolite
clasto-lactacystin  -lactone induced apoptotic death in CLL
but not in normal lymphocytes. This difference was completely abolished
when tripeptide aldehydes such as MG132 or LLnL (which can also inhibit
calpains) were used as less specific proteasomal inhibitors. Moreover,
B-CLL cells exhibited a constitutive altered ubiquitin-proteasome
system, including a threefold higher chymotrypsin-like proteasomal
activity and high levels of nuclear ubiquitin-conjugated proteins
compared with normal lymphocytes. Interestingly, B-CLL cells also
displayed altered proteolytic regulation of wild-type p53, an apoptotic
factor reported to be a substrate for the ubiquitin-proteasome system.
Nuclear wild-type p53 accumulated after lactacystin treatment used at
the discriminating concentration in malignant, but not in normal,
lymphocytes. In contrast, p53 was stabilized by MG132 or LLnL in
malignant and normal cells undergoing apoptosis, indicating that in
normal lymphocytes p53 is regulated mainly by calpains and not by the
ubiquitin-proteasome system. This work raises the possibility that two
different proteolytic pathways controlling p53 stability may be
pathologically imbalanced. This could result in modification of
apoptosis control, since in CLL-lymphocytes a highly upregulated
ubiquitin-proteasome system, which controls p53 stability among other
apoptotic factors, was correlated with an increased propensity of these
cells to apoptosis triggered by lactacystin.
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